Compositions and methods relating to breast specific genes and proteins

ABSTRACT

The present invention relates to newly identified nucleic acids and polypeptides present in normal and neoplastic breast cells, including fragments, variants and derivatives of the nucleic acids and polypeptides. The present invention also relates to antibodies to the polypeptides of the invention, as well as agonists and antagonists of the polypeptides of the invention. The invention also relates to compositions comprising the nucleic acids, polypeptides, antibodies, variants, derivatives, agonists and antagonists of the invention and methods for the use of these compositions. These uses include identifying, diagnosing, monitoring, staging, imaging and treating breast cancer and noncancerous disease states in breast tissue, identifying breast tissue, monitoring and identifying and/or designing agonists and antagonists of polypeptides of the invention. The uses also include gene therapy, production of transgenic animals and cells, and production of engineered breast tissue for treatment and research.

[0001] This application claims the benefit of priority from U.S. Provisional Application Serial No. 60/268,292 filed Feb. 13, 2001, which is herein incorporated by reference in its entirety.

FIELD OF THE INVENTION

[0002] The present invention relates to newly identified nucleic acid molecules and polypeptides present in normal and neoplastic breast cells, including fragments, variants and derivatives of the nucleic acids and polypeptides. The present invention also relates to antibodies to the polypeptides of the invention, as well as agonists and antagonists of the polypeptides of the invention. The invention also relates to compositions comprising the nucleic acids, polypeptides, antibodies, variants, derivatives, agonists and antagonists of the invention and methods for the use of these compositions. These uses include identifying, diagnosing, monitoring, staging, imaging and treating breast cancer and noncancerous disease states in breast tissue, identifying breast tissue and monitoring and identifying and/or designing agonists and antagonists of polypeptides of the invention. The uses also include gene therapy, production of transgenic animals and cells, and production of engineered breast tissue for treatment and research.

BACKGROUND OF THE INVENTION

[0003] Excluding skin cancer, breast cancer, also called mammary tumor, is the most common cancer among women, accounting for a third of the cancers diagnosed in the United States. One in nine women will develop breast cancer in her lifetime and about 192,000 new cases of breast cancer are diagnosed annually with about 42,000 deaths. Bevers, Primary Prevention of Breast Cancer, in BREAST CANCER, 20-54 (Kelly K Hunt et al., ed., 2001); Kochanek et al., 49 Nat'l.Vital Statistics Reports 1, 14 (2001).

[0004] In the treatment of breast cancer, there is considerable emphasis on detection and risk assessment because early and accurate staging of breast cancer has a significant impact on survival. For example, breast cancer detected at an early stage (stage T0, discussed below) has a five-year survival rate of 92%. Conversely, if the cancer is not detected until a late stage (i.e., stage T4), the five-year survival rate is reduced to 13%. AJCC Cancer Staging Handbook pp. 164-65 (Irvin D. Fleming et al. eds., 5^(th) ed. 1998). Some detection techniques, such as mammography and biopsy, involve increased discomfort, expense, and/or radiation, and are only prescribed only to patients with an increased risk of breast cancer.

[0005] Current methods for predicting or detecting breast cancer risk are not optimal. One method for predicting the relative risk of breast cancer is by examining a patient's risk factors and pursuing aggressive diagnostic and treatment regiments for high risk patients. A patient's risk of breast cancer has been positively associated with increasing age, nulliparity, family history of breast cancer, personal history of breast cancer, early menarche, late menopause, late age of first full term pregnancy, prior proliferative breast disease, irradiation of the breast at an early age and a personal history of malignancy. Lifestyle factors such as fat consumption, alcohol consumption, education, and socioeconomic status have also been associated with an increased incidence of breast cancer although a direct cause and effect relationship has not been established. While these risk factors are statistically significant, their weak association with breast cancer limited their usefulness. Most women who develop breast cancer have none of the risk factors listed above, other than the risk that comes with growing older. NIH Publication No. 00-1556 (2000).

[0006] Current screening methods for detecting cancer, such as breast self exam, ultrasound, and mammography have drawbacks that reduce their effectiveness or prevent their widespread adoption. Breast self exams, while useful, are unreliable for the detection of breast cancer in the initial stages where the tumor is small and difficult to detect by palpitation. Ultrasound measurements require skilled operators at an increased expense. Mammography, while sensitive, is subject to over diagnosis in the detection of lesions that have questionable malignant potential. There is also the fear of the radiation used in mammography because prior chest radiation is a factor associated with an increase incidence of breast cancer.

[0007] At this time, there are no adequate methods of breast cancer prevention. The current methods of breast cancer prevention involve prophylactic mastectomy (mastectomy performed before cancer diagnosis) and chemoprevention (chemotherapy before cancer diagnosis) which are drastic measures that limit their adoption even among women with increased risk of breast cancer. Bevers, supra.

[0008] A number of genetic markers have been associated with breast cancer. Examples of these markers include carcinoembryonic antigen (CEA) (Mughal et al., 249 JAMA 1881 (1983)) MUC-1 (Frische and Liu, 22 J. Clin. Ligand 320 (2000)), HER-2/neu (Haris et al., 15 Proc.Am.Soc.Clin.Oncology. A96 (1996)), uPA, PAI-1, LPA, LPC, RAK and BRCA (Esteva and Fritsche, Serum and Tissue Markers for Breast Cancer, in BREAST CANCER, 286-308 (2001)). These markers have problems with limited sensitivity, low correlation, and false negatives which limit their use for initial diagnosis. For example, while the BRCA1 gene mutation is useful as an indicator of an increased risk for breast cancer, it has limited use in cancer diagnosis because only 6.2% of breast cancers are BRCA1 positive. Malone et al., 279 JAMA 922 (1998). See also, Mewman et al., 279 JAMA 915 (1998) (correlation of only 3.3%).

[0009] Breast cancers are diagnosed into the appropriate stage categories recognizing that different treatments are more effective for different stages of cancer. Stage TX indicates that primary tumor cannot be assessed (i.e., tumor was removed or breast tissue was removed). Stage T0 is characterized by abnormalities such as hyperplasia but with no evidence of primary tumor. Stage Tis is characterized by carcinoma in situ, intraductal carcinoma, lobular carcinoma in situ, or Paget's disease of the nipple with no tumor. Stage T1 is characterized as having a tumor of 2 cm or less in the greatest dimension. Within stage T1, Tmic indicates microinvasion of 0.1 cm or less, T1a indicates a tumor of between 0.1 to 0.5 cm, T1b indicates a tumor of between 0.5 to 1 cm, and T1c indicates tumors of between 1 cm to 2 cm. Stage T2 is characterized by tumors from 2 cm to 5 cm in the greatest dimension. Tumors greater than 5 cm in size are classified as stage T4. Within stage T4, T4a indicates extension of the tumor to the chess wall, T4b indicates edema or ulceration of the skin of the breast or satellite skin nodules confined to the same breast, T4c indicates a combination of T4a and T4b, and T4d indicates inflammatory carcinoma. AJCC Cancer Staging Handbook pp. 159-70 (Irvin D. Fleming et al. eds., 5^(th) ed. 1998). In addition to standard staging, breast tumors may be classified according to their estrogen receptor and progesterone receptor protein status. Fisher et al., 7 Breast Cancer Research and Treatment 147 (1986). Additional pathological status, such as HER2/neu status may also be useful. Thor et al., 90 J.Nat'l.Cancer Inst. 1346 (1998); Paik et al., 90 J.Nat'l.Cancer Inst. 1361 (1998); Hutchins et al., 17 Proc.Am.Soc.Clin.Oncology A2 (1998).; and Simpson et al., 18 J.Clin.Oncology 2059 (2000).

[0010] In addition to the staging of the primary tumor, breast cancer metastases to regional lymph nodes may be staged. Stage NX indicates that the lymph nodes cannot be assessed (e.g., previously removed). Stage NO indicates no regional lymph node metastasis. Stage N1 indicates metastasis to movable ipsilateral axillary lymph nodes. Stage N2 indicates metastasis to ipsilateral axillary lymph nodes fixed to one another or to other structures. Stage N3 indicates metastasis to ipsilateral internal mammary lymph nodes. Id.

[0011] Stage determination has potential prognostic value and provides criteria for designing optimal therapy. Simpson et al., 18 J. Clin. Oncology 2059 (2000). Generally, pathological staging of breast cancer is preferable to clinical staging because the former gives a more accurate prognosis. However, clinical staging would be preferred if it were as accurate as pathological staging because it does not depend on an invasive procedure to obtain tissue for pathological evaluation. Staging of breast cancer would be improved by detecting new markers in cells, tissues, or bodily fluids which could differentiate between different stages of invasion. Progress in this field will allow more rapid and reliable method for treating breast cancer patients.

[0012] Treatment of breast cancer is generally decided after an accurate staging of the primary tumor. Primary treatment options include breast conserving therapy (lumpectomy, breast irradiation, and surgical staging of the axilla), and modified radical mastectomy. Additional treatments include chemotherapy, regional irradiation, and, in extreme cases, terminating estrogen production by ovarian ablation.

[0013] Until recently, the customary treatment for all breast cancer was mastectomy. Fonseca et al., 127 Annals of Internal Medicine 1013 (1997). However, recent data indicate that less radical procedures may be equally effective, in terms of survival, for early stage breast cancer. Fisher et al., 16 J. of Clinical Oncology 441(1998). The treatment options for a patient with early stage breast cancer (i.e., stage Tis) may be breast-sparing surgery followed by localized radiation therapy at the breast. Alternatively, mastectomy optionally coupled with radiation or breast reconstruction may be employed. These treatment methods are equally effective in the early stages of breast cancer.

[0014] Patients with stage I and stage II breast cancer require surgery with chemotherapy and/or hormonal therapy. Surgery is of limited use in Stage III and stage IV patients. Thus, these patients are better candidates for chemotherapy and radiation therapy with surgery limited to biopsy to permit initial staging or subsequent restaging because cancer is rarely curative at this stage of the disease. AJCC Cancer Staging Handbook 84, ¶. 164-65 (Irvin D. Fleming et al. eds., 5^(th) ed. 1998).

[0015] In an effort to provide more treatment options to patients, efforts are underway to define an earlier stage of breast cancer with low recurrence which could be treated with lumpectomy without postoperative radiation treatment. While a number of attempts have been made to classify early stage breast cancer, no consensus recommendation on postoperative radiation treatment has been obtained from these studies. Page et al., 75 Cancer 1219 (1995); Fisher et al., 75 Cancer 1223 (1995); Silverstein et al., 77 Cancer 2267 (1996).

[0016] As discussed above, each of the methods for diagnosing and staging breast cancer is limited by the technology employed. Accordingly, there is need for sensitive molecular and cellular markers for the detection of breast cancer. There is a need for molecular markers for the accurate staging, including clinical and pathological staging, of breast cancers to optimize treatment methods. Finally, there is a need for sensitive molecular and cellular markers to monitor the progress of cancer treatments, including markers that can detect recurrence of breast cancers following remission.

[0017] Other objects, features, advantages and aspects of the present invention will become apparent to those of skill in the art from the following description. It should be understood, however, that the following description and the specific examples, while indicating preferred embodiments of the invention, are given by way of illustration only. Various changes and modifications within the spirit and scope of the disclosed invention will become readily apparent to those skilled in the art from reading the following description and from reading the other parts of the present disclosure.

SUMMARY OF THE INVENTION

[0018] The present invention solves these and other needs in the art by providing nucleic acid molecules and polypeptides as well as antibodies, agonists and antagonists, thereto that may be used to identify, diagnose, monitor, stage, image and treat breast cancer and non-cancerous disease states in breast; identify and monitor breast tissue; and identify and design agonists and antagonists of polypeptides of the invention. The invention also provides gene therapy, methods for producing transgenic animals and cells, and methods for producing engineered breast tissue for treatment and research.

[0019] Accordingly, one object of the invention is to provide nucleic acid molecules that are specific to breast cells and/or breast tissue. These breast specific nucleic acids (BSNAs) may be a naturally-occurring cDNA, genomic DNA, RNA, or a fragment of one of these nucleic acids, or may be a non-naturally-occurring nucleic acid molecule. If the BSNA is genomic DNA, then the BSNA is a breast specific gene (BSG). In a preferred embodiment, the nucleic acid molecule encodes a polypeptide that is specific to breast. In a more preferred embodiment, the nucleic acid molecule encodes a polypeptide that comprises an amino acid sequence of SEQ ID NO: 172 through 295. In another highly preferred embodiment, the nucleic acid molecule comprises a nucleic acid sequence of SEQ ID NO: 1 through 171. By nucleic acid molecule, it is also meant to be inclusive of sequences that selectively hybridize or exhibit substantial sequence similarity to a nucleic acid molecule encoding a BSP, or that selectively hybridize or exhibit substantial sequence similarity to a BSNA, as well as allelic variants of a nucleic acid molecule encoding a BSP, and allelic variants of a BSNA. Nucleic acid molecules comprising a part of a nucleic acid sequence that encodes a BSP or that comprises a part of a nucleic acid sequence of a BSNA are also provided.

[0020] A related object of the present invention is to provide a nucleic acid molecule comprising one or more expression control sequences controlling the transcription and/or translation of all or a part of a BSNA. In a preferred embodiment, the nucleic acid molecule comprises one or more expression control sequences controlling the transcription and/or translation of a nucleic acid molecule that encodes all or a fragment of a BSP.

[0021] Another object of the invention is to provide vectors and/or host cells comprising a nucleic acid molecule of the instant invention. In a preferred embodiment, the nucleic acid molecule encodes all or a fragment of a BSP. In another preferred embodiment, the nucleic acid molecule comprises all or a part of a BSNA.

[0022] Another object of the invention is to provided methods for using the vectors and host cells comprising a nucleic acid molecule of the instant invention to recombinantly produce polypeptides of the invention.

[0023] Another object of the invention is to provide a polypeptide encoded by a nucleic acid molecule of the invention. In a preferred embodiment, the polypeptide is a BSP. The polypeptide may comprise either a fragment or a full-length protein as well as a mutant protein (mutein), fusion protein, homologous protein or a polypeptide encoded by an allelic variant of a BSP.

[0024] Another object of the invention is to provide an antibody that specifically binds to a polypeptide of the instant invention.

[0025] Another object of the invention is to provide agonists and antagonists of the nucleic acid molecules and polypeptides of the instant invention.

[0026] Another object of the invention is to provide methods for using the nucleic acid molecules to detect or amplify nucleic acid molecules that have similar or identical nucleic acid sequences compared to the nucleic acid molecules described herein. In a preferred embodiment, the invention provides methods of using the nucleic acid molecules of the invention for identifying, diagnosing, monitoring, staging, imaging and treating breast cancer and non-cancerous disease states in breast. In another preferred embodiment, the invention provides methods of using the nucleic acid molecules of the invention for identifying and/or monitoring breast tissue. The nucleic acid molecules of the instant invention may also be used in gene therapy, for producing transgenic animals and cells, and for producing engineered breast tissue for treatment and research.

[0027] The polypeptides and/or antibodies of the instant invention may also be used to identify, diagnose, monitor, stage, image and treat breast cancer and noncancerous disease states in breast. The invention provides methods of using the polypeptides of the invention to identify and/or monitor breast tissue, and to produce engineered breast tissue.

[0028] The agonists and antagonists of the instant invention may be used to treat breast cancer and non-cancerous disease states in breast and to produce engineered breast tissue.

[0029] Yet another object of the invention is to provide a computer readable means of storing the nucleic acid and amino acid sequences of the invention. The records of the computer readable means can be accessed for reading and displaying of sequences for comparison, alignment and ordering of the sequences of the invention to other sequences.

DETAILED DESCRIPTION OF THE INVENTION

[0030] Definitions and General Techniques

[0031] Unless otherwise defined herein, scientific and technical terms used in connection with the present invention shall have the meanings that are commonly understood by those of ordinary skill in the art. Further, unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular. Generally, nomenclatures used in connection with, and techniques of, cell and tissue culture, molecular biology, immunology, microbiology, genetics and protein and nucleic acid chemistry and hybridization described herein are those well-known and commonly used in the art. The methods and techniques of the present invention are generally performed according to conventional methods well-known in the art and as described in various general and more specific references that are cited and discussed throughout the present specification unless otherwise indicated. See, e.g., Sambrook et al., Molecular Cloning: A Laboratory Manual, 2d ed., Cold Spring Harbor Laboratory Press (1989) and Sambrook et al., Molecular Cloning: A Laboratory Manual, 3d ed., Cold Spring Harbor Press (2001); Ausubel et al., Current Protocols in Molecular Biology, Greene Publishing Associates (1992, and Supplements to 2000); Ausubel et al., Short Protocols in Molecular Biology: A Compendium of Methods from Current Protocols in Molecular Biology—4^(th) Ed., Wiley & Sons (1999); Harlow and Lane, Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory Press (1990); and Harlow and Lane, Using Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory Press (1999); each of which is incorporated herein by reference in its entirety.

[0032] Enzymatic reactions and purification techniques are performed according to manufacturer's specifications, as commonly accomplished in the art or as described herein. The nomenclatures used in connection with, and the laboratory procedures and techniques of, analytical chemistry, synthetic organic chemistry, and medicinal and pharmaceutical chemistry described herein are those well-known and commonly used in the art. Standard techniques are used for chemical syntheses, chemical analyses, pharmaceutical preparation, formulation, and delivery, and treatment of patients.

[0033] The following terms, unless otherwise indicated, shall be understood to have the following meanings:

[0034] A “nucleic acid molecule” of this invention refers to a polymeric form of nucleotides and includes both sense and antisense strands of RNA, cDNA, genomic DNA, and synthetic forms and mixed polymers of the above. A nucleotide refers to a ribonucleotide, deoxynucleotide or a modified form of either type of nucleotide. A “nucleic acid molecule” as used herein is synonymous with “nucleic acid” and “polynucleotide.” The term “nucleic acid molecule” usually refers to a molecule of at least 10 bases in length, unless otherwise specified. The term includes single- and double-stranded forms of DNA. In addition, a polynucleotide may include either or both naturally-occurring and modified nucleotides linked together by naturally-occurring and/or non-naturally occurring nucleotide linkages.

[0035] The nucleic acid molecules may be modified chemically or biochemically or may contain non-natural or derivatized nucleotide bases, as will be readily appreciated by those of skill in the art. Such modifications include, for example, labels, methylation, substitution of one or more of the naturally occurring nucleotides with an analog, internucleotide modifications such as uncharged linkages (e.g., methyl phosphonates, phosphotriesters, phosphoramidates, carbamates, etc.), charged linkages (e.g., phosphorothioates, phosphorodithioates, etc.), pendent moieties (e.g., polypeptides), intercalators (e.g., acridine, psoralen, etc.), chelators, alkylators, and modified linkages (e.g., alpha anomeric nucleic acids, etc.) The term “nucleic acid molecule” also includes any topological conformation, including single-stranded, double-stranded, partially duplexed, triplexed, hairpinned, circular and padlocked conformations. Also included are synthetic molecules that mimic polynucleotides in their ability to bind to a designated sequence via hydrogen bonding and other chemical interactions. Such molecules are known in the art and include, for example, those in which peptide linkages substitute for phosphate linkages in the backbone of the molecule.

[0036] A “gene” is defined as a nucleic acid molecule that comprises a nucleic acid sequence that encodes a polypeptide and the expression control sequences that surround the nucleic acid sequence that encodes the polypeptide. For instance, a gene may comprise a promoter, one or more enhancers, a nucleic acid sequence that encodes a polypeptide, downstream regulatory sequences and, possibly, other nucleic acid sequences involved in regulation of the expression of an RNA. As is well-known in the art, eukaryotic genes usually contain both exons and introns. The term “exon” refers to a nucleic acid sequence found in genomic DNA that is bioinformatically predicted and/or experimentally confirmed to contribute a contiguous sequence to a mature mRNA transcript. The term “intron” refers to a nucleic acid sequence found in genomic DNA that is predicted and/or confirmed to not contribute to a mature mRNA transcript, but rather to be “spliced out” during processing of the transcript.

[0037] A nucleic acid molecule or polypeptide is “derived” from a particular species if the nucleic acid molecule or polypeptide has been isolated from the particular species, or if the nucleic acid molecule or polypeptide is homologous to a nucleic acid molecule or polypeptide isolated from a particular species.

[0038] An “isolated” or “substantially pure” nucleic acid or polynucleotide (e.g., an RNA, DNA or a mixed polymer) is one which is substantially separated from other cellular components that naturally accompany the native polynucleotide in its natural host cell, e.g., ribosomes, polymerases, or genomic sequences with which it is naturally associated. The term embraces a nucleic acid or polynucleotide that (1) has been removed from its naturally occurring environment, (2) is not associated with all or a portion of a polynucleotide in which the “isolated polynucleotide” is found in nature, (3) is operatively linked to a polynucleotide which it is not linked to in nature, (4) does not occur in nature as part of a larger sequence or (5) includes nucleotides or internucleoside bonds that are not found in nature. The term “isolated” or “substantially pure” also can be used in reference to recombinant or cloned DNA isolates, chemically synthesized polynucleotide analogs, or polynucleotide analogs that are biologically synthesized by heterologous systems. The term “isolated nucleic acid molecule” includes nucleic acid molecules that are integrated into a host cell chromosome at a heterologous site, recombinant fusions of a native fragment to a heterologous sequence, recombinant vectors present as episomes or as integrated into a host cell chromosome.

[0039] A “part” of a nucleic acid molecule refers to a nucleic acid molecule that comprises a partial contiguous sequence of at least 10 bases of the reference nucleic acid molecule. Preferably, a part comprises at least 15 to 20 bases of a reference nucleic acid molecule. In theory, a nucleic acid sequence of 17 nucleotides is of sufficient length to occur at random less frequently than once in the three gigabase human genome, and thus to provide a nucleic acid probe that can uniquely identify the reference sequence in a nucleic acid mixture of genomic complexity. A preferred part is one that comprises a nucleic acid sequence that can encode at least 6 contiguous amino acid sequences (fragments of at least 18 nucleotides) because they are useful in directing the expression or synthesis of peptides that are useful in mapping the epitopes of the polypeptide encoded by the reference nucleic acid. See, e.g., Geysen et al., Proc. Natl. Acad. Sci. USA 81:3998-4002 (1984); and U.S. Pat. Nos. 4,708,871 and 5,595,915, the disclosures of which are incorporated herein by reference in their entireties. A part may also comprise at least 25, 30, 35 or 40 nucleotides of a reference nucleic acid molecule, or at least 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400 or 500 nucleotides of a reference nucleic acid molecule. A part of a nucleic acid molecule may comprise no other nucleic acid sequences. Alternatively, a part of a nucleic acid may comprise other nucleic acid sequences from other nucleic acid molecules.

[0040] The term “oligonucleotide” refers to a nucleic acid molecule generally comprising a length of 200 bases or fewer. The term often refers to single-stranded deoxyribonucleotides, but it can refer as well to single- or double-stranded ribonucleotides, RNA:DNA hybrids and double-stranded DNAs, among others. Preferably, oligonucleotides are 10 to 60 bases in length and most preferably 12, 13, 14, 15, 16, 17, 18, 19 or 20 bases in length. Other preferred oligonucleotides are 25, 30, 35, 40, 45, 50, 55 or 60 bases in length. Oligonucleotides may be single-stranded, e.g. for use as probes or primers, or may be double-stranded, e.g. for use in the construction of a mutant gene. Oligonucleotides of the invention can be either sense or antisense oligonucleotides. An oligonucleotide can be derivatized or modified as discussed above for nucleic acid molecules.

[0041] Oligonucleotides, such as single-stranded DNA probe oligonucleotides, often are synthesized by chemical methods, such as those implemented on automated oligonucleotide synthesizers. However, oligonucleotides can be made by a variety of other methods, including in vitro recombinant DNA-mediated techniques and by expression of DNAs in cells and organisms. Initially, chemically synthesized DNAs typically are obtained without a 5′ phosphate. The 5′ ends of such oligonucleotides are not substrates for phosphodiester bond formation by ligation reactions that employ DNA ligases typically used to form recombinant DNA molecules. Where ligation of such oligonucleotides is desired, a phosphate can be added by standard techniques, such as those that employ a kinase and ATP. The 3′ end of a chemically synthesized oligonucleotide generally has a free hydroxyl group and, in the presence of a ligase, such as T4 DNA ligase, readily will form a phosphodiester bond with a 5′ phosphate of another polynucleotide, such as another oligonucleotide. As is well-known, this reaction can be prevented selectively, where desired, by removing the 5′ phosphates of the other polynucleotide(s) prior to ligation.

[0042] The term “naturally-occurring nucleotide” referred to herein includes naturally-occurring deoxyribonucleotides and ribonucleotides. The term “modified nucleotides” referred to herein includes nucleotides with modified or substituted sugar groups and the like. The term “nucleotide linkages” referred to herein includes nucleotides linkages such as phosphorothioate, phosphorodithioate, phosphoroselenoate, phosphorodiselenoate, phosphoroanilothioate, phoshoraniladate, phosphoroamidate, and the like. See e.g., LaPlanche et al. Nucl. Acids Res. 14:9081-9093 (1986); Stein et al. Nucl Acids Res. 16:3209-3221 (1988); Zon et al. Anti-Cancer Drug Design 6:539-568 (1991); Zon et al., in Eckstein (ed.) Oligonucleotides and Analogues: A Practical Approach, pp. 87-108, Oxford University Press (1991); U.S. Pat. No. 5,151,510; Uhlmann and Peyman Chemical Reviews 90:543 (1990), the disclosures of which are hereby incorporated by reference.

[0043] Unless specified otherwise, the left hand end of a polynucleotide sequence in sense orientation is the 5′ end and the right hand end of the sequence is the 3′ end. In addition, the left hand direction of a polynucleotide sequence in sense orientation is referred to as the 5′ direction, while the right hand direction of the polynucleotide sequence is referred to as the 3′ direction. Further, unless otherwise indicated, each nucleotide sequence is set forth herein as a sequence of deoxyribonucleotides. It is intended, however, that the given sequence be interpreted as would be appropriate to the polynucleotide composition: for example, if the isolated nucleic acid is composed of RNA, the given sequence intends ribonucleotides, with uridine substituted for thymidine.

[0044] The term “allelic variant” refers to one of two or more alternative naturally-occurring forms of a gene, wherein each gene possesses a unique nucleotide sequence. In a preferred embodiment, different alleles of a given gene have similar or identical biological properties.

[0045] The term “percent sequence identity” in the context of nucleic acid sequences refers to the residues in two sequences which are the same when aligned for maximum correspondence. The length of sequence identity comparison may be over a stretch of at least about nine nucleotides, usually at least about 20 nucleotides, more usually at least about 24 nucleotides, typically at least about 28 nucleotides, more typically at least about 32 nucleotides, and preferably at least about 36 or more nucleotides. There are a number of different algorithms known in the art which can be used to measure nucleotide sequence identity. For instance, polynucleotide sequences can be compared using FASTA, Gap or Bestfit, which are programs in Wisconsin Package Version 10.0, Genetics Computer Group (GCG), Madison, Wis. FASTA, which includes, e.g., the programs FASTA2 and FASTA3, provides alignments and percent sequence identity of the regions of the best overlap between the query and search sequences (Pearson, Methods Enzymol. 183: 63-98 (1990); Pearson, Methods Mol. Biol. 132: 185-219 (2000); Pearson, Methods Enzymol. 266: 227-258 (1996); Pearson, J. Mol. Biol. 276: 71-84 (1998); herein incorporated by reference). Unless otherwise specified, default parameters for a particular program or algorithm are used. For instance, percent sequence identity between nucleic acid sequences can be determined using FASTA with its default parameters (a word size of 6 and the NOPAM factor for the scoring matrix) or using Gap with its default parameters as provided in GCG Version 6.1, herein incorporated by reference.

[0046] A reference to a nucleic acid sequence encompasses its complement unless otherwise specified. Thus, a reference to a nucleic acid molecule having a particular sequence should be understood to encompass its complementary strand, with its complementary sequence. The complementary strand is also useful, e.g., for antisense therapy, hybridization probes and PCR primers.

[0047] In the molecular biology art, researchers use the terms “percent sequence identity”, “percent sequence similarity” and “percent sequence homology” interchangeably. In this application, these terms shall have the same meaning with respect to nucleic acid sequences only.

[0048] The term “substantial similarity” or “substantial sequence similarity,” when referring to a nucleic acid or fragment thereof, indicates that, when optimally aligned with appropriate nucleotide insertions or deletions with another nucleic acid (or its complementary strand), there is nucleotide sequence identity in at least about 50%, more preferably 60% of the nucleotide bases, usually at least about 70%, more usually at least about 80%, preferably at least about 90%, and more preferably at least about 95-98% of the nucleotide bases, as measured by any well-known algorithm of sequence identity, such as FASTA, BLAST or Gap, as discussed above.

[0049] Alternatively, substantial similarity exists when a nucleic acid or fragment thereof hybridizes to another nucleic acid, to a strand of another nucleic acid, or to the complementary strand thereof, under selective hybridization conditions. Typically, selective hybridization will occur when there is at least about 55% sequence identity, preferably at least about 65%, more preferably at least about 75%, and most preferably at least about 90% sequence identity, over a stretch of at least about 14 nucleotides, more preferably at least 17 nucleotides, even more preferably at least 20, 25, 30, 35, 40, 50, 60, 70, 80, 90 or 100 nucleotides.

[0050] Nucleic acid hybridization will be affected by such conditions as salt concentration, temperature, solvents, the base composition of the hybridizing species, length of the complementary regions, and the number of nucleotide base mismatches between the hybridizing nucleic acids, as will be readily appreciated by those skilled in the art. “Stringent hybridization conditions” and “stringent wash conditions” in the context of nucleic acid hybridization experiments depend upon a number of different physical parameters. The most important parameters include temperature of hybridization, base composition of the nucleic acids, salt concentration and length of the nucleic acid. One having ordinary skill in the art knows how to vary these parameters to achieve a particular stringency of hybridization. In general, “stringent hybridization” is performed at about 25° C. below the thermal melting point (T_(m)) for the specific DNA hybrid under a particular set of conditions. “Stringent washing” is performed at temperatures about 5° C. lower than the T_(m) for the specific DNA hybrid under a particular set of conditions. The T_(m) is the temperature at which 50% of the target sequence hybridizes to a perfectly matched probe. See Sambrook (1989), supra, p. 9.51, hereby incorporated by reference.

[0051] The T_(m) for a particular DNA-DNA hybrid can be estimated by the formula:

T _(m)=81.5° C.+16.6(log ₁₀[Na⁺])+0.41(fraction G+C)−0.63(% formamide)−(600/l)

[0052] where l is the length of the hybrid in base pairs.

[0053] The T_(m) for a particular RNA-RNA hybrid can be estimated by the formula:

T _(m)=79.8° C.+18.5(log ₁₀[Na⁺])+0.58(fraction G+C)+11.8(fraction G+C)²−0.35(% formamide)−(820/l).

[0054] The T_(m) for a particular RNA-DNA hybrid can be estimated by the formula:

T _(m)=79.8° C.+18.5(log ₁₀[Na⁺])+0.58(fraction G+C)+11.8(fraction G+C)²−0.50(% formamide)−(820/l).

[0055] In general, the T_(m) decreases by 1-1.5° C. for each 1% of mismatch between two nucleic acid sequences. Thus, one having ordinary skill in the art can alter hybridization and/or washing conditions to obtain sequences that have higher or lower degrees of sequence identity to the target nucleic acid. For instance, to obtain hybridizing nucleic acids that contain up to 10% mismatch from the target nucleic acid sequence, 10-15° C. would be subtracted from the calculated T_(m) of a perfectly matched hybrid, and then the hybridization and washing temperatures adjusted accordingly. Probe sequences may also hybridize specifically to duplex DNA under certain conditions to form triplex or other higher order DNA complexes. The preparation of such probes and suitable hybridization conditions are well-known in the art.

[0056] An example of stringent hybridization conditions for hybridization of complementary nucleic acid sequences having more than 100 complementary residues on a filter in a Southern or Northern blot or for screening a library is 50% formamide/6× SSC at 42° C. for at least ten hours and preferably overnight (approximately 16 hours). Another example of stringent hybridization conditions is 6× SSC at 68° C. without formamide for at least ten hours and preferably overnight. An example of moderate stringency hybridization conditions is 6× SSC at 55° C. without formamide for at least ten hours and preferably overnight. An example of low stringency hybridization conditions for hybridization of complementary nucleic acid sequences having more than 100 complementary residues on a filter in a Southern or Northern blot or for screening a library is 6× SSC at 42° C. for at least ten hours. Hybridization conditions to identify nucleic acid sequences that are similar but not identical can be identified by experimentally changing the hybridization temperature from 68° C. to 42° C. while keeping the salt concentration constant (6× SSC), or keeping the hybridization temperature and salt concentration constant (e.g. 42° C. and 6× SSC) and varying the formamide concentration from 50% to 0%. Hybridization buffers may also include blocking agents to lower background. These agents are well-known in the art. See Sambrook et al. (1989), supra, pages 8.46 and 9.46-9.58, herein incorporated by reference. See also Ausubel (1992), supra, Ausubel (1999), supra, and Sambrook (2001), supra.

[0057] Wash conditions also can be altered to change stringency conditions. An example of stringent wash conditions is a 0.2× SSC wash at 65° C. for 15 minutes (see Sambrook (1989), supra, for SSC buffer). Often the high stringency wash is preceded by a low stringency wash to remove excess probe. An exemplary medium stringency wash for duplex DNA of more than 100 base pairs is 1× SSC at 45° C. for 15 minutes. An exemplary low stringency wash for such a duplex is 4× SSC at 40° C. for 15 minutes. In general, signal-to-noise ratio of 2× or higher than that observed for an unrelated probe in the particular hybridization assay indicates detection of a specific hybridization.

[0058] As defined herein, nucleic acid molecules that do not hybridize to each other under stringent conditions are still substantially similar to one another if they encode polypeptides that are substantially identical to each other. This occurs, for example, when a nucleic acid molecule is created synthetically or recombinantly using high codon degeneracy as permitted by the redundancy of the genetic code.

[0059] Hybridization conditions for nucleic acid molecules that are shorter than 100 nucleotides in length (e.g., for oligonucleotide probes) may be calculated by the formula:

T _(m)=81.5° C.+16.6(log ₁₀[Na⁺])+0.41(fraction G+C)−(600/N),

[0060] wherein N is change length and the [Na⁺] is 1 M or less. See Sambrook (1989), supra, p. 11.46. For hybridization of probes shorter than 100 nucleotides, hybridization is usually performed under stringent conditions (5-10° C. below the T_(m)) using high concentrations (0.1-1.0 pmol/ml) of probe. Id. at p. 11.45. Determination of hybridization using mismatched probes, pools of degenerate probes or “guessmers,” as well as hybridization solutions and methods for empirically determining hybridization conditions are well-known in the art. See, e.g., Ausubel (1999), supra; Sambrook (1989), supra, pp. 11.45-11.57.

[0061] The term “digestion” or “digestion of DNA” refers to catalytic cleavage of the DNA with a restriction enzyme that acts only at certain sequences in the DNA. The various restriction enzymes referred to herein are commercially available and their reaction conditions, cofactors and other requirements for use are known and routine to the skilled artisan. For analytical purposes, typically, 1 μg of plasmid or DNA fragment is digested with about 2 units of enzyme in about 20 μl of reaction buffer. For the purpose of isolating DNA fragments for plasmid construction, typically 5 to 50 μg of DNA are digested with 20 to 250 units of enzyme in proportionately larger volumes. Appropriate buffers and substrate amounts for particular restriction enzymes are described in standard laboratory manuals, such as those referenced below, and they are specified by commercial suppliers. Incubation times of about 1 hour at 37° C. are ordinarily used, but conditions may vary in accordance with standard procedures, the supplier's instructions and the particulars of the reaction. After digestion, reactions may be analyzed, and fragments may be purified by electrophoresis through an agarose or polyacrylamide gel, using well-known methods that are routine for those skilled in the art.

[0062] The term “ligation” refers to the process of forming phosphodiester bonds between two or more polynucleotides, which most often are double-stranded DNAS. Techniques for ligation are well-known to the art and protocols for ligation are described in standard laboratory manuals and references, such as, e.g., Sambrook (1989), supra.

[0063] Genome-derived “single exon probes,” are probes that comprise at least part of an exon (“reference exon”) and can hybridize detectably under high stringency conditions to transcript-derived nucleic acids that include the reference exon but do not hybridize detectably under high stringency conditions to nucleic acids that lack the reference exon. Single exon probes typically further comprise, contiguous to a first end of the exon portion, a first intronic and/or intergenic sequence that is identically contiguous to the exon in the genome, and may contain a second intronic and/or intergenic sequence that is identically contiguous to the exon in the genome. The minimum length of genome-derived single exon probes is defined by the requirement that the exonic portion be of sufficient length to hybridize under high stringency conditions to transcript-derived nucleic acids, as discussed above. The maximum length of genome-derived single exon probes is defined by the requirement that the probes contain portions of no more than one exon. The single exon probes may contain priming sequences not found in contiguity with the rest of the probe sequence in the genome, which priming sequences are useful for PCR and other amplification-based technologies.

[0064] The term “microarray” or “nucleic acid microarray” refers to a substrate-bound collection of plural nucleic acids, hybridization to each of the plurality of bound nucleic acids being separately detectable. The substrate can be solid or porous, planar or non-planar, unitary or distributed. Microarrays or nucleic acid microarrays include all the devices so called in Schena (ed.), DNA Microarrays: A Practical Approach (Practical Approach Series), Oxford University Press (1999); Nature Genet. 21(1)(suppl.):1-60 (1999); Schena (ed.), Microarray Biochip: Tools and Technology, Eaton Publishing Company/BioTechniques Books Division (2000). These microarrays include substrate-bound collections of plural nucleic acids in which the plurality of nucleic acids are disposed on a plurality of beads, rather than on a unitary planar substrate, as is described, inter alia, in Brenner et al., Proc. Natl. Acad. Sci. USA 97(4):1665-1670 (2000).

[0065] The term “mutated” when applied to nucleic acid molecules means that nucleotides in the nucleic acid sequence of the nucleic acid molecule may be inserted, deleted or changed compared to a reference nucleic acid sequence. A single alteration may be made at a locus (a point mutation) or multiple nucleotides may be inserted, deleted or changed at a single locus. In addition, one or more alterations may be made at any number of loci within a nucleic acid sequence. In a preferred embodiment, the nucleic acid molecule comprises the wild type nucleic acid sequence encoding a BSP or is a BSNA. The nucleic acid molecule may be mutated by any method known in the art including those mutagenesis techniques described infra.

[0066] The term “error-prone PCR” refers to a process for performing PCR under conditions where the copying fidelity of the DNA polymerase is low, such that a high rate of point mutations is obtained along the entire length of the PCR product. See, e.g., Leung et al., Technique 1: 11-15 (1989) and Caldwell et al., PCR Methods Applic. 2: 28-33 (1992).

[0067] The term “oligonucleotide-directed mutagenesis” refers to a process which enables the generation of site-specific mutations in any cloned DNA segment of interest. See, e.g., Reidhaar-Olson et al., Science 241: 53-57 (1988).

[0068] The term “assembly PCR” refers to a process which involves the assembly of a PCR product from a mixture of small DNA fragments. A large number of different PCR reactions occur in parallel in the same vial, with the products of one reaction priming the products of another reaction.

[0069] The term “sexual PCR mutagenesis” or “DNA shuffling” refers to a method of error-prone PCR coupled with forced homologous recombination between DNA molecules of different but highly related DNA sequence in vitro, caused by random fragmentation of the DNA molecule based on sequence similarity, followed by fixation of the crossover by primer extension in an error-prone PCR reaction. See, e.g., Stemmer, Proc. Natl. Acad. Sci. U.S.A. 91: 10747-10751 (1994). DNA shuffling can be carried out between several related genes (“Family shuffling”).

[0070] The term “in vivo mutagenesis” refers to a process of generating random mutations in any cloned DNA of interest which involves the propagation of the DNA in a strain of bacteria such as E. coli that carries mutations in one or more of the DNA repair pathways. These “mutator” strains have a higher random mutation rate than that of a wild-type parent. Propagating the DNA in a mutator strain will eventually generate random mutations within the DNA.

[0071] The term “cassette mutagenesis” refers to any process for replacing a small region of a double-stranded DNA molecule with a synthetic oligonucleotide “cassette” that differs from the native sequence. The oligonucleotide often contains completely and/or partially randomized native sequence.

[0072] The term “recursive ensemble mutagenesis” refers to an algorithm for protein engineering (protein mutagenesis) developed to produce diverse populations of phenotypically related mutants whose members differ in amino acid sequence. This method uses a feedback mechanism to control successive rounds of combinatorial cassette mutagenesis. See, e.g., Arkin et al., Proc. Natl. Acad. Sci. U.S.A. 89: 7811-7815 (1992).

[0073] The term “exponential ensemble mutagenesis” refers to a process for generating combinatorial libraries with a high percentage of unique and functional mutants, wherein small groups of residues are randomized in parallel to identify, at each altered position, amino acids which lead to functional proteins. See, e.g., Delegrave et al., Biotechnology Research 11: 1548-1552 (1993); Arnold, Current Opinion in Biotechnology 4: 450-455 (1993). Each of the references mentioned above are hereby incorporated by reference in its entirety.

[0074] “Operatively linked” expression control sequences refers to a linkage in which the expression control sequence is contiguous with the gene of interest to control the gene of interest, as well as expression control sequences that act in trans or at a distance to control the gene of interest.

[0075] The term “expression control sequence” as used herein refers to polynucleotide sequences which are necessary to affect the expression of coding sequences to which they are operatively linked. Expression control sequences are sequences which control the transcription, post-transcriptional events and translation of nucleic acid sequences. Expression control sequences include appropriate transcription initiation, termination, promoter and enhancer sequences; efficient RNA processing signals such as splicing and polyadenylation signals; sequences that stabilize cytoplasmic mRNA; sequences that enhance translation efficiency (e.g., ribosome binding sites); sequences that enhance protein stability; and when desired, sequences that enhance protein secretion. The nature of such control sequences differs depending upon the host organism; in prokaryotes, such control sequences generally include the promoter, ribosomal binding site, and transcription termination sequence. The term “control sequences” is intended to include, at a minimum, all components whose presence is essential for expression, and can also include additional components whose presence is advantageous, for example, leader sequences and fusion partner sequences.

[0076] The term “vector,” as used herein, is intended to refer to a nucleic acid molecule capable of transporting another nucleic acid to which it has been linked. One type of vector is a “plasmid”, which refers to a circular double-stranded DNA loop into which additional DNA segments may be ligated. Other vectors include cosmids, bacterial artificial chromosomes (BAC) and yeast artificial chromosomes (YAC). Another type of vector is a viral vector, wherein additional DNA segments may be ligated into the viral genome. Viral vectors that infect bacterial cells are referred to as bacteriophages. Certain vectors are capable of autonomous replication in a host cell into which they are introduced (e.g., bacterial vectors having a bacterial origin of replication). Other vectors can be integrated into the genome of a host cell upon introduction into the host cell, and thereby are replicated along with the host genome. Moreover, certain vectors are capable of directing the expression of genes to which they are operatively linked. Such vectors are referred to herein as “recombinant expression vectors” (or simply, “expression vectors”). In general, expression vectors of utility in recombinant DNA techniques are often in the form of plasmids. In the present specification, “plasmid” and “vector” may be used interchangeably as the plasmid is the most commonly used form of vector. However, the invention is intended to include other forms of expression vectors that serve equivalent functions.

[0077] The term “recombinant host cell” (or simply “host cell”), as used herein, is intended to refer to a cell into which an expression vector has been introduced. It should be understood that such terms are intended to refer not only to the particular subject cell but to the progeny of such a cell. Because certain modifications may occur in succeeding generations due to either mutation or environmental influences, such progeny may not, in fact, be identical to the parent cell, but are still included within the scope of the term “host cell” as used herein.

[0078] As used herein, the phrase “open reading frame” and the equivalent acronym “ORF” refer to that portion of a transcript-derived nucleic acid that can be translated in its entirety into a sequence of contiguous amino acids. As so defined, an ORF has length, measured in nucleotides, exactly divisible by 3. As so defined, an ORF need not encode the entirety of a natural protein.

[0079] As used herein, the phrase “ORF-encoded peptide” refers to the predicted or actual translation of an ORF.

[0080] As used herein, the phrase “degenerate variant” of a reference nucleic acid sequence intends all nucleic acid sequences that can be directly translated, using the standard genetic code, to provide an amino acid sequence identical to that translated from the reference nucleic acid sequence.

[0081] The term “polypeptide” encompasses both naturally-occurring and non-naturally-occurring proteins and polypeptides, polypeptide fragments and polypeptide mutants, derivatives and analogs. A polypeptide may be monomeric or polymeric. Further, a polypeptide may comprise a number of different modules within a single polypeptide each of which has one or more distinct activities. A preferred polypeptide in accordance with the invention comprises a BSP encoded by a nucleic acid molecule of the instant invention, as well as a fragment, mutant, analog and derivative thereof.

[0082] The term “isolated protein” or “isolated polypeptide” is a protein or polypeptide that by virtue of its origin or source of derivation (1) is not associated with naturally associated components that accompany it in its native state, (2) is free of other proteins from the same species (3) is expressed by a cell from a different species, or (4) does not occur in nature. Thus, a polypeptide that is chemically synthesized or synthesized in a cellular system different from the cell from which it naturally originates will be “isolated” from its naturally associated components. A polypeptide or protein may also be rendered substantially free of naturally associated components by isolation, using protein purification techniques well-known in the art.

[0083] A protein or polypeptide is “substantially pure,” “substantially homogeneous” or “substantially purified” when at least about 60% to 75% of a sample exhibits a single species of polypeptide. The polypeptide or protein may be monomeric or multimeric. A substantially pure polypeptide or protein will typically comprise about 50%, 60%, 70%, 80% or 90% W/W of a protein sample, more usually about 95%, and preferably will be over 99% pure. Protein purity or homogeneity may be indicated by a number of means well-known in the art, such as polyacrylamide gel electrophoresis of a protein sample, followed by visualizing a single polypeptide band upon staining the gel with a stain well-known in the art. For certain purposes, higher resolution may be provided by using HPLC or other means well-known in the art for purification.

[0084] The term “polypeptide fragment” as used herein refers to a polypeptide of the instant invention that has an amino-terminal and/or carboxy-terminal deletion compared to a full-length polypeptide. In a preferred embodiment, the polypeptide fragment is a contiguous sequence in which the amino acid sequence of the fragment is identical to the corresponding positions in the naturally-occurring sequence. Fragments typically are at least 5, 6, 7, 8, 9 or 10 amino acids long, preferably at least 12, 14, 16 or 18 amino acids long, more preferably at least 20 amino acids long, more preferably at least 25, 30, 35, 40 or 45, amino acids, even more preferably at least 50 or 60 amino acids long, and even more preferably at least 70 amino acids long.

[0085] A “derivative” refers to polypeptides or fragments thereof that are substantially similar in primary structural sequence but which include, e.g., in vivo or in vitro chemical and biochemical modifications that are not found in the native polypeptide. Such modifications include, for example, acetylation, acylation, ADP-ribosylation, amidation, covalent attachment of flavin, covalent attachment of a heme moiety, covalent attachment of a nucleotide or nucleotide derivative, covalent attachment of a lipid or lipid derivative, covalent attachment of phosphotidylinositol, cross-linking, cyclization, disulfide bond formation, demethylation, formation of covalent cross-links, formation of cystine, formation of pyroglutamate, formylation, gamma-carboxylation, glycosylation, GPI anchor formation, hydroxylation, iodination, methylation, myristoylation, oxidation, proteolytic processing, phosphorylation, prenylation, racemization, selenoylation, sulfation, transfer-RNA mediated addition of amino acids to proteins such as arginylation, and ubiquitination. Other modification include, e.g., labeling with radionuclides, and various enzymatic modifications, as will be readily appreciated by those skilled in the art. A variety of methods for labeling polypeptides and of substituents or labels useful for such purposes are well-known in the art, and include radioactive isotopes such as ¹²⁵I, ³²P, ³⁵S, and ³H, ligands which bind to labeled antiligands (e.g., antibodies), fluorophores, chemiluminescent agents, enzymes, and antiligands which can serve as specific binding pair members for a labeled ligand. The choice of label depends on the sensitivity required, ease of conjugation with the primer, stability requirements, and available instrumentation. Methods for labeling polypeptides are well-known in the art. See Ausubel (1992), supra; Ausubel (1999), supra, herein incorporated by reference.

[0086] The term “fusion protein” refers to polypeptides of the instant invention comprising polypeptides or fragments coupled to heterologous amino acid sequences. Fusion proteins are useful because they can be constructed to contain two or more desired functional elements from two or more different proteins. A fusion protein comprises at least 10 contiguous amino acids from a polypeptide of interest, more preferably at least 20 or 30 amino acids, even more preferably at least 40, 50 or 60 amino acids, yet more preferably at least 75, 100 or 125 amino acids. Fusion proteins can be produced recombinantly by constructing a nucleic acid sequence which encodes the polypeptide or a fragment thereof in frame with a nucleic acid sequence encoding a different protein or peptide and then expressing the fusion protein. Alternatively, a fusion protein can be produced chemically by crosslinking the polypeptide or a fragment thereof to another protein.

[0087] The term “analog” refers to both polypeptide analogs and non-peptide analogs. The term “polypeptide analog” as used herein refers to a polypeptide of the instant invention that is comprised of a segment of at least 25 amino acids that has substantial identity to a portion of an amino acid sequence but which contains non-natural amino acids or non-natural inter-residue bonds. In a preferred embodiment, the analog has the same or similar biological activity as the native polypeptide. Typically, polypeptide analogs comprise a conservative amino acid substitution (or insertion or deletion) with respect to the naturally-occurring sequence. Analogs typically are at least 20 amino acids long, preferably at least 50 amino acids long or longer, and can often be as long as a full-length naturally-occurring polypeptide.

[0088] The term “non-peptide analog” refers to a compound with properties that are analogous to those of a reference polypeptide of the instant invention. A non-peptide compound may also be termed a “peptide mimetic” or a “peptidomimetic.” Such compounds are often developed with the aid of computerized molecular modeling. Peptide mimetics that are structurally similar to useful peptides may be used to produce an equivalent effect. Generally, peptidomimetics are structurally similar to a paradigm polypeptide (i.e., a polypeptide that has a desired biochemical property or pharmacological activity), but have one or more peptide linkages optionally replaced by a linkage selected from the group consisting of: —CH₂NH—, —CH₂S—, —CH₂—CH₂—, —CH═CH-(cis and trans), —COCH₂—, —CH(OH)CH₂—, and —CH₂SO—, by methods well-known in the art. Systematic substitution of one or more amino acids of a consensus sequence with a D-amino acid of the same type (e.g., D-lysine in place of L-lysine) may also be used to generate more stable peptides. In addition, constrained peptides comprising a consensus sequence or a substantially identical consensus sequence variation may be generated by methods known in the art (Rizo et al., Ann. Rev. Biochem. 61:387-418 (1992), incorporated herein by reference). For example, one may add internal cysteine residues capable of forming intramolecular disulfide bridges which cyclize the peptide.

[0089] A “polypeptide mutant” or “mutein” refers to a polypeptide of the instant invention whose sequence contains substitutions, insertions or deletions of one or more amino acids compared to the amino acid sequence of a native or wild-type protein. A mutein may have one or more amino acid point substitutions, in which a single amino acid at a position has been changed to another amino acid, one or more insertions and/or deletions, in which one or more amino acids are inserted or deleted, respectively, in the sequence of the naturally-occurring protein, and/or truncations of the amino acid sequence at either or both the amino or carboxy termini. Further, a mutein may have the same or different biological activity as the naturally-occurring protein. For instance, a mutein may have an increased or decreased biological activity. A mutein has at least 50% sequence similarity to the wild type protein, preferred is 60% sequence similarity, more preferred is 70% sequence similarity. Even more preferred are muteins having 80%, 85% or 90% sequence similarity to the wild type protein. In an even more preferred embodiment, a mutein exhibits 95% sequence identity, even more preferably 97%, even more preferably 98% and even more preferably 99%. Sequence similarity may be measured by any common sequence analysis algorithm, such as Gap or Bestfit.

[0090] Preferred amino acid substitutions are those which: (1) reduce susceptibility to proteolysis, (2) reduce susceptibility to oxidation, (3) alter binding affinity for forming protein complexes, (4) alter binding affinity or enzymatic activity, and (5) confer or modify other physicochemical or functional properties of such analogs. For example, single or multiple amino acid substitutions (preferably conservative amino acid substitutions) may be made in the naturally-occurring sequence (preferably in the portion of the polypeptide outside the domain(s) forming intermolecular contacts. In a preferred embodiment, the amino acid substitutions are moderately conservative substitutions or conservative substitutions. In a more preferred embodiment, the amino acid substitutions are conservative substitutions. A conservative amino acid substitution should not substantially change the structural characteristics of the parent sequence (e.g., a replacement amino acid should not tend to disrupt a helix that occurs in the parent sequence, or disrupt other types of secondary structure that characterizes the parent sequence). Examples of art-recognized polypeptide secondary and tertiary structures are described in Creighton (ed.), Proteins, Structures and Molecular Principles, W. H. Freeman and Company (1984); Branden et al. (ed.), Introduction to Protein Structure, Garland Publishing (1991); Thornton et al., Nature 354:105-106 (1991), each of which are incorporated herein by reference.

[0091] As used herein, the twenty conventional amino acids and their abbreviations follow conventional usage. See Golub et al. (eds.), Immunology—A Synthesis 2^(nd) Ed., Sinauer Associates (1991), which is incorporated herein by reference. Stereoisomers (e.g., D-amino acids) of the twenty conventional amino acids, unnatural amino acids such as α-, α-disubstituted amino acids, N-alkyl amino acids, and other unconventional amino acids may also be suitable components for polypeptides of the present invention. Examples of unconventional amino acids include: 4-hydroxyproline, γ-carboxyglutamate, ε-N,N,N-trimethyllysine, ε-N-acetyllysine, O-phosphoserine, N-acetylserine, N-formylmethionine, 3-methylhistidine, 5-hydroxylysine, s-N-methylarginine, and other similar amino acids and imino acids (e.g., 4-hydroxyproline). In the polypeptide notation used herein, the lefthand direction is the amino terminal direction and the right hand direction is the carboxy-terminal direction, in accordance with standard usage and convention.

[0092] A protein has “homology” or is “homologous” to a protein from another organism if the encoded amino acid sequence of the protein has a similar sequence to the encoded amino acid sequence of a protein of a different organism and has a similar biological activity or function. Alternatively, a protein may have homology or be homologous to another protein if the two proteins have similar amino acid sequences and have similar biological activities or functions. Although two proteins are said to be “homologous,” this does not imply that there is necessarily an evolutionary relationship between the proteins. Instead, the term “homologous” is defined to mean that the two proteins have similar amino acid sequences and similar biological activities or functions. In a preferred embodiment, a homologous protein is one that exhibits 50% sequence similarity to the wild type protein, preferred is 60% sequence similarity, more preferred is 70% sequence similarity. Even more preferred are homologous proteins that exhibit 80%, 85% or 90% sequence similarity to the wild type protein. In a yet more preferred embodiment, a homologous protein exhibits 95%, 97%, 98% or 99% sequence similarity.

[0093] When “sequence similarity” is used in reference to proteins or peptides, it is recognized that residue positions that are not identical often differ by conservative amino acid substitutions. In a preferred embodiment, a polypeptide that has “sequence similarity” comprises conservative or moderately conservative amino acid substitutions. A “conservative amino acid substitution” is one in which an amino acid residue is substituted by another amino acid residue having a side chain (R group) with similar chemical properties (e.g., charge or hydrophobicity). In general, a conservative amino acid substitution will not substantially change the functional properties of a protein. In cases where two or more amino acid sequences differ from each other by conservative substitutions, the percent sequence identity or degree of similarity may be adjusted upwards to correct for the conservative nature of the substitution. Means for making this adjustment are well-known to those of skill in the art. See, e.g., Pearson, Methods Mol. Biol. 24: 307-31 (1994), herein incorporated by reference.

[0094] For instance, the following six groups each contain amino acids that are conservative substitutions for one another:

[0095] 1) Serine (S), Threonine (T);

[0096] 2) Aspartic Acid (D), Glutamic Acid (E);

[0097] 3) Asparagine (N), Glutamine (Q);

[0098] 4) Arginine (R), Lysine (K);

[0099] 5) Isoleucine (I), Leucine (L), Methionine (M), Alanine (A), Valine (V), and

[0100] 6) Phenylalanine (F), Tyrosine (Y), Tryptophan (W).

[0101] Alternatively, a conservative replacement is any change having a positive value in the PAM250 log-likelihood matrix disclosed in Gonnet et al., Science 256: 1443-45 (1992), herein incorporated by reference. A “moderately conservative” replacement is any change having a nonnegative value in the PAM250 log-likelihood matrix.

[0102] Sequence similarity for polypeptides, which is also referred to as sequence identity, is typically measured using sequence analysis software. Protein analysis software matches similar sequences using measures of similarity assigned to various substitutions, deletions and other modifications, including conservative amino acid substitutions. For instance, GCG contains programs such as “Gap” and “Bestfit” which can be used with default parameters to determine sequence homology or sequence identity between closely related polypeptides, such as homologous polypeptides from different species of organisms or between a wild type protein and a mutein thereof. See, e.g., GCG Version 6.1. Other programs include FASTA, discussed supra.

[0103] A preferred algorithm when comparing a sequence of the invention to a database containing a large number of sequences from different organisms is the computer program BLAST, especially blastp or tblastn. See, e.g., Altschul et al., J. Mol. Biol. 215: 403-410 (1990); Altschul et al., Nucleic Acids Res. 25:3389-402 (1997); herein incorporated by reference. Preferred parameters for blastp are: Expectation value:  10 (default) Filter: seg (default) Cost to open a gap:  11 (default) Cost to extend a gap:  1 (default) Max. alignments: 100 (default) Word size:  11 (default) No. of descriptions: 100 (default) Penalty Matrix: BLOSUM62

[0104] The length of polypeptide sequences compared for homology will generally be at least about 16 amino acid residues, usually at least about 20 residues, more usually at least about 24 residues, typically at least about 28 residues, and preferably more than about 35 residues. When searching a database containing sequences from a large number of different organisms, it is preferable to compare amino acid sequences.

[0105] Database searching using amino acid sequences can be measured by algorithms other than blastp are known in the art. For instance, polypeptide sequences can be compared using FASTA, a program in GCG Version 6.1. FASTA (e.g., FASTA2 and FASTA3) provides alignments and percent sequence identity of the regions of the best overlap between the query and search sequences (Pearson (1990), supra; Pearson (2000), supra. For example, percent sequence identity between amino acid sequences can be determined using FASTA with its default or recommended parameters (a word size of 2 and the PAM250 scoring matrix), as provided in GCG Version 6.1, herein incorporated by reference.

[0106] An “antibody” refers to an intact immunoglobulin, or to an antigen-binding portion thereof that competes with the intact antibody for specific binding to a molecular species, e.g., a polypeptide of the instant invention. Antigen-binding portions may be produced by recombinant DNA techniques or by enzymatic or chemical cleavage of intact antibodies. Antigen-binding portions include, inter alia, Fab, Fab′, F(ab′)₂, Fv, dAb, and complementarity determining region (CDR) fragments, single-chain antibodies (scFv), chimeric antibodies, diabodies and polypeptides that contain at least a portion of an immunoglobulin that is sufficient to confer specific antigen binding to the polypeptide. An Fab fragment is a monovalent fragment consisting of the VL, VH, CL and CH1 domains; an F(ab′)₂ fragment is a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; an Fd fragment consists of the VH and CH1 domains; an Fv fragment consists of the VL and VH domains of a single arm of an antibody; and a dAb fragment consists of a VH domain. See, e.g., Ward et al., Nature 341: 544-546 (1989).

[0107] By “bind specifically” and “specific binding” is here intended the ability of the antibody to bind to a first molecular species in preference to binding to other molecular species with which the antibody and first molecular species are admixed. An antibody is said specifically to “recognize” a first molecular species when it can bind specifically to that first molecular species.

[0108] A single-chain antibody (scFv) is an antibody in which a VL and VH region are paired to form a monovalent molecule via a synthetic linker that enables them to be made as a single protein chain. See, e.g., Bird et al., Science 242: 423-426 (1988); Huston et al., Proc. Natl. Acad. Sci. USA 85: 5879-5883 (1988). Diabodies are bivalent, bispecific antibodies in which VH and VL domains are expressed on a single polypeptide chain, but using a linker that is too short to allow for pairing between the two domains on the same chain, thereby forcing the domains to pair with complementary domains of another chain and creating two antigen binding sites. See e.g., Holliger et al., Proc. Natl. Acad. Sci. USA 90: 6444-6448 (1993); Poljak et al., Structure 2: 1121-1123 (1994). One or more CDRs may be incorporated into a molecule either covalently or noncovalently to make it an immunoadhesin. An immunoadhesin may incorporate the CDR(s) as part of a larger polypeptide chain, may covalently link the CDR(s) to another polypeptide chain, or may incorporate the CDR(s) noncovalently. The CDRs permit the immunoadhesin to specifically bind to a particular antigen of interest. A chimeric antibody is an antibody that contains one or more regions from one antibody and one or more regions from one or more other antibodies.

[0109] An antibody may have one or more binding sites. If there is more than one binding site, the binding sites may be identical to one another or may be different. For instance, a naturally-occurring immunoglobulin has two identical binding sites, a single-chain antibody or Fab fragment has one binding site, while a “bispecific” or “bifunctional” antibody has two different binding sites.

[0110] An “isolated antibody” is an antibody that (1) is not associated with naturally-associated components, including other naturally-associated antibodies, that accompany it in its native state, (2) is free of other proteins from the same species, (3) is expressed by a cell from a different species, or (4) does not occur in nature. It is known that purified proteins, including purified antibodies, may be stabilized with non-naturally-associated components. The non-naturally-associated component may be a protein, such as albumin (e.g., BSA) or a chemical such as polyethylene glycol (PEG).

[0111] A “neutralizing antibody” or “an inhibitory antibody” is an antibody that inhibits the activity of a polypeptide or blocks the binding of a polypeptide to a ligand that normally binds to it. An “activating antibody” is an antibody that increases the activity of a polypeptide.

[0112] The term “epitope” includes any protein determinant capable of specifically binding to an immunoglobulin or T-cell receptor. Epitopic determinants usually consist of chemically active surface groupings of molecules such as amino acids or sugar side chains and usually have specific three-dimensional structural characteristics, as well as specific charge characteristics. An antibody is said to specifically bind an antigen when the dissociation constant is less than1 μM, preferably less than100 nM and most preferably less than 10 nM.

[0113] The term “patient” as used herein includes human and veterinary subjects.

[0114] Throughout this specification and claims, the word “comprise,” or variations such as “comprises” or “comprising,” will be understood to imply the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers.

[0115] The term “breast specific” refers to a nucleic acid molecule or polypeptide that is expressed predominantly in the breast as compared to other tissues in the body. In a preferred embodiment, a “breast specific” nucleic acid molecule or polypeptide is expressed at a level that is 5-fold higher than any other tissue in the body. In a more preferred embodiment, the “breast specific” nucleic acid molecule or polypeptide is expressed at a level that is 10-fold higher than any other tissue in the body, more preferably at least 15-fold, 20-fold, 25-fold, 50-fold or 100-fold higher than any other tissue in the body. Nucleic acid molecule levels may be measured by nucleic acid hybridization, such as Northern blot hybridization, or quantitative PCR. Polypeptide levels may be measured by any method known to accurately quantitate protein levels, such as Western blot analysis.

[0116] Nucleic Acid Molecules Regulatory Sequences, Vectors Host Cells and Recombinant Methods of Making Polypeptides

[0117] Nucleic Acid Molecules

[0118] One aspect of the invention provides isolated nucleic acid molecules that are specific to the breast or to breast cells or tissue or that are derived from such nucleic acid molecules. These isolated breast specific nucleic acids (BSNAs) may comprise a cDNA, a genomic DNA, RNA, or a fragment of one of these nucleic acids, or may be a non-naturally-occurring nucleic acid molecule. In a preferred embodiment, the nucleic acid molecule encodes a polypeptide that is specific to breast, a breast-specific polypeptide (BSP). In a more preferred embodiment, the nucleic acid molecule encodes a polypeptide that comprises an amino acid sequence of SEQ ID NO: 172 through 295. In another highly preferred embodiment, the nucleic acid molecule comprises a nucleic acid sequence of SEQ ID NO: 1 through 171.

[0119] A BSNA may be derived from a human or from another animal. In a preferred embodiment, the BSNA is derived from a human or other mammal. In a more preferred embodiment, the BSNA is derived from a human or other primate. In an even more preferred embodiment, the BSNA is derived from a human.

[0120] By “nucleic acid molecule” for purposes of the present invention, it is also meant to be inclusive of nucleic acid sequences that selectively hybridize to a nucleic acid molecule encoding a BSNA or a complement thereof. The hybridizing nucleic acid molecule may or may not encode a polypeptide or may not encode a BSP. However, in a preferred embodiment, the hybridizing nucleic acid molecule encodes a BSP. In a more preferred embodiment, the invention provides a nucleic acid molecule that selectively hybridizes to a nucleic acid molecule that encodes a polypeptide comprising an amino acid sequence of SEQ ID NO: 172 through 295. In an even more preferred embodiment, the invention provides a nucleic acid molecule that selectively hybridizes to a nucleic acid molecule comprising the nucleic acid sequence of SEQ ID NO: 1 through 171.

[0121] In a preferred embodiment, the nucleic acid molecule selectively hybridizes to a nucleic acid molecule encoding a BSP under low stringency conditions. In a more preferred embodiment, the nucleic acid molecule selectively hybridizes to a nucleic acid molecule encoding a BSP under moderate stringency conditions. In a more preferred embodiment, the nucleic acid molecule selectively hybridizes to a nucleic acid molecule encoding a BSP under high stringency conditions. In an even more preferred embodiment, the nucleic acid molecule hybridizes under low, moderate or high stringency conditions to a nucleic acid molecule encoding a polypeptide comprising an amino acid sequence of SEQ ID NO: 172 through 295. In a yet more preferred embodiment, the nucleic acid molecule hybridizes under low, moderate or high stringency conditions to a nucleic acid molecule comprising a nucleic acid sequence selected from SEQ ID NO: 1 through 171. In a preferred embodiment of the invention, the hybridizing nucleic acid molecule may be used to express recombinantly a polypeptide of the invention.

[0122] By “nucleic acid molecule” as used herein it is also meant to be inclusive of sequences that exhibits substantial sequence similarity to a nucleic acid encoding a BSP or a complement of the encoding nucleic acid molecule. In a preferred embodiment, the nucleic acid molecule exhibits substantial sequence similarity to a nucleic acid molecule encoding human BSP. In a more preferred embodiment, the nucleic acid molecule exhibits substantial sequence similarity to a nucleic acid molecule encoding a polypeptide having an amino acid sequence of SEQ ID NO: 172 through 295. In a preferred embodiment, the similar nucleic acid molecule is one that has at least 60% sequence identity with a nucleic acid molecule encoding a BSP, such as a polypeptide having an amino acid sequence of SEQ ID NO: 172 through 295, more preferably at least 70%, even more preferably at least 80% and even more preferably at least 85%. In a more preferred embodiment, the similar nucleic acid molecule is one that has at least 90% sequence identity with a nucleic acid molecule encoding a BSP, more preferably at least 95%, more preferably at least 97%, even more preferably at least 98%, and still more preferably at least 99%. In another highly preferred embodiment, the nucleic acid molecule is one that has at least 99.5%, 99.6%, 99.7%, 99.8% or 99.9% sequence identity with a nucleic acid molecule encoding a BSP.

[0123] In another preferred embodiment, the nucleic acid molecule exhibits substantial sequence similarity to a BSNA or its complement. In a more preferred embodiment, the nucleic acid molecule exhibits substantial sequence similarity to a nucleic acid molecule comprising a nucleic acid sequence of SEQ ID NO: 1 through 171. In a preferred embodiment, the nucleic acid molecule is one that has at least 60% sequence identity with a BSNA, such as one having a nucleic acid sequence of SEQ ID NO: 1 through 171, more preferably at least 70%, even more preferably at least 80% and even more preferably at least 85%. In a more preferred embodiment, the nucleic acid molecule is one that has at least 90% sequence identity with a BSNA, more preferably at least 95%, more preferably at least 97%, even more preferably at least 98%, and still more preferably at least 99%. In another highly preferred embodiment, the nucleic acid molecule is one that has at least 99.5%, 99.6%, 99.7%, 99.8% or 99.9% sequence identity with a BSNA.

[0124] A nucleic acid molecule that exhibits substantial sequence similarity may be one that exhibits sequence identity over its entire length to a BSNA or to a nucleic acid molecule encoding a BSP, or may be one that is similar over only a part of its length. In this case, the part is at least 50 nucleotides of the BSNA or the nucleic acid molecule encoding a BSP, preferably at least 100 nucleotides, more preferably at least 150 or 200 nucleotides, even more preferably at least 250 or 300 nucleotides, still more preferably at least 400 or 500 nucleotides.

[0125] The substantially similar nucleic acid molecule may be a naturally-occurring one that is derived from another species, especially one derived from another primate, wherein the similar nucleic acid molecule encodes an amino acid sequence that exhibits significant sequence identity to that of SEQ ID NO: 172 through 295 or demonstrates significant sequence identity to the nucleotide sequence of SEQ ID NO: 1 through 171. The similar nucleic acid molecule may also be a naturally-occurring nucleic acid molecule from a human, when the BSNA is a member of a gene family. The similar nucleic acid molecule may also be a naturally-occurring nucleic acid molecule derived from a non-primate, mammalian species, including without limitation, domesticated species, e.g., dog, cat, mouse, rat, rabbit, hamster, cow, horse and pig; and wild animals, e.g., monkey, fox, lions, tigers, bears, giraffes, zebras, etc. The substantially similar nucleic acid molecule may also be a naturally-occurring nucleic acid molecule derived from a non-mammalian species, such as birds or reptiles. The naturally-occurring substantially similar nucleic acid molecule may be isolated directly from humans or other species. In another embodiment, the substantially similar nucleic acid molecule may be one that is experimentally produced by random mutation of a nucleic acid molecule. In another embodiment, the substantially similar nucleic acid molecule may be one that is experimentally produced by directed mutation of a BSNA. Further, the substantially similar nucleic acid molecule may or may not be a BSNA. However, in a preferred embodiment, the substantially similar nucleic acid molecule is a BSNA.

[0126] By “nucleic acid molecule” it is also meant to be inclusive of allelic variants of a BSNA or a nucleic acid encoding a BSP. For instance, single nucleotide polymorphisms (SNPs) occur frequently in eukaryotic genomes. In fact, more than 1.4 million SNPs have already identified in the human genome, International Human Genome Sequencing Consortium, Nature 409: 860-921 (2001). Thus, the sequence determined from one individual of a species may differ from other allelic forms present within the population. Additionally, small deletions and insertions, rather than single nucleotide polymorphisms, are not uncommon in the general population, and often do not alter the function of the protein. Further, amino acid substitutions occur frequently among natural allelic variants, and often do not substantially change protein function.

[0127] In a preferred embodiment, the nucleic acid molecule comprising an allelic variant is a variant of a gene, wherein the gene is transcribed into an mRNA that encodes a BSP. In a more preferred embodiment, the gene is transcribed into an mRNA that encodes a BSP comprising an amino acid sequence of SEQ ID NO: 172 through 295. In another preferred embodiment, the allelic variant is a variant of a gene, wherein the gene is transcribed into an mRNA that is a BSNA. In a more preferred embodiment, the gene is transcribed into an mRNA that comprises the nucleic acid sequence of SEQ ID NO: 1 through 171. In a preferred embodiment, the allelic variant is a naturally-occurring allelic variant in the species of interest. In a more preferred embodiment, the species of interest is human.

[0128] By “nucleic acid molecule” it is also meant to be inclusive of a part of a nucleic acid sequence of the instant invention. The part may or may not encode a polypeptide, and may or may not encode a polypeptide that is a BSP. However, in a preferred embodiment, the part encodes a BSP. In one aspect, the invention comprises a part of a BSNA. In a second aspect, the invention comprises a part of a nucleic acid molecule that hybridizes or exhibits substantial sequence similarity to a BSNA. In a third aspect, the invention comprises a part of a nucleic acid molecule that is an allelic variant of a BSNA. In a fourth aspect, the invention comprises a part of a nucleic acid molecule that encodes a BSP. A part comprises at least 10 nucleotides, more preferably at least 15, 17, 18, 20, 25, 30, 35, 40, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400 or 500 nucleotides. The maximum size of a nucleic acid part is one nucleotide shorter than the sequence of the nucleic acid molecule encoding the full-length protein.

[0129] By “nucleic acid molecule” it is also meant to be inclusive of sequence that encoding a fusion protein, a homologous protein, a polypeptide fragment, a mutein or a polypeptide analog, as described below.

[0130] Nucleotide sequences of the instantly-described nucleic acids were determined by sequencing a DNA molecule that had resulted, directly or indirectly, from at least one enzymatic polymerization reaction (e.g., reverse transcription and/or polymerase chain reaction) using an automated sequencer (such as the MegaBACE™ 1000, Molecular Dynamics, Sunnyvale, Calif., USA). Further, all amino acid sequences of the polypeptides of the present invention were predicted by translation from the nucleic acid sequences so determined, unless otherwise specified.

[0131] In a preferred embodiment of the invention, the nucleic acid molecule contains modifications of the native nucleic acid molecule. These modifications include normative internucleoside bonds, post-synthetic modifications or altered nucleotide analogues. One having ordinary skill in the art would recognize that the type of modification that can be made will depend upon the intended use of the nucleic acid molecule. For instance, when the nucleic acid molecule is used as a hybridization probe, the range of such modifications will be limited to those that permit sequence-discriminating base pairing of the resulting nucleic acid. When used to direct expression of RNA or protein in vitro or in vivo, the range of such modifications will be limited to those that permit the nucleic acid to function properly as a polymerization substrate. When the isolated nucleic acid is used as a therapeutic agent, the modifications will be limited to those that do not confer toxicity upon the isolated nucleic acid.

[0132] In a preferred embodiment, isolated nucleic acid molecules can include nucleotide analogues that incorporate labels that are directly detectable, such as radiolabels or fluorophores, or nucleotide analogues that incorporate labels that can be visualized in a subsequent reaction, such as biotin or various haptens. In a more preferred embodiment, the labeled nucleic acid molecule may be used as a hybridization probe.

[0133] Common radiolabeled analogues include those labeled with ³³P, ³²P, and ³⁵S, such as α-³²P-dATP, α-³²P-dCTP, α-³²P-dGTP, α-³²P-dTTP, α-³²P-3′dATP, α-³²P-ATP, α-³²P-CTP, α-³²P-GTP, α-³²P-UTP, α-³⁵S-dATP, α-³⁵S-GTP, α-³³P-dATP, and the like.

[0134] Commercially available fluorescent nucleotide analogues readily incorporated into the nucleic acids of the present invention include Cy3-dCTP, Cy3-dUTP, Cy5-dCTP, Cy3-dUTP (Amersham Pharmacia Biotech, Piscataway, N.J., USA), fluorescein-12-dUTP, tetramethylrhodamine-6-dUTP, Texas Red®-5-dUTP, Cascade Blue® -7-dUTP, BODIPY® FL-14-dUTP, BODIPY® TMR-14-dUTP, BODIPY® TR-14-dUTP, Rhodamine Green™-5-dUTP, Oregon Green® 488-5-dUTP, Texas Red®-12-dUTP, BODIPY® 630/650-14-dUTP, BODIPY® 650/665-14-dUTP, Alexa Fluor® 488-5-dUTP, Alexa Fluor® 532-5-dUTP, Alexa Fluor® 568-5-dUTP, Alexa Fluor® 594-5-dUTP, Alexa Fluor® 546-14-dUTP, fluorescein-12-UTP, tetramethylrhodamine-6-UTP, Texas Red®-5-UTP, Cascade Blue®-7-UTP, BODIPY® FL-14-UTP, BODIPY® TMR-14-UTP, BODIPY® TR-14-UTP, Rhodamine Green™-5-UTP, Alexa Fluor® 488-5-UTP, Alexa Fluor® 546-14-UTP (Molecular Probes, Inc. Eugene, Oreg., USA). One may also custom synthesize nucleotides having other fluorophores. See Henegariu et al., Nature Biotechnol. 18: 345-348 (2000), the disclosure of which is incorporated herein by reference in its entirety.

[0135] Haptens that are commonly conjugated to nucleotides for subsequent labeling include biotin (biotin-11-dUTP, Molecular Probes, Inc., Eugene, Oreg., USA; biotin-21-UTP, biotin-21-dUTP, Clontech Laboratories, Inc., Palo Alto, Calif., USA), digoxigenin (DIG-11-dUTP, alkali labile, DIG-11-UTP, Roche Diagnostics Corp., Indianapolis, Ind., USA), and dinitrophenyl (dinitrophenyl-11-dUTP, Molecular Probes, Inc., Eugene, Oreg., USA).

[0136] Nucleic acid molecules can be labeled by incorporation of labeled nucleotide analogues into the nucleic acid. Such analogues can be incorporated by enzymatic polymerization, such as by nick translation, random priming, polymerase chain reaction (PCR), terminal transferase tailing, and end-filling of overhangs, for DNA molecules, and in vitro transcription driven, e.g., from phage promoters, such as T7, T3, and SP6, for RNA molecules. Commercial kits are readily available for each such labeling approach. Analogues can also be incorporated during automated solid phase chemical synthesis. Labels can also be incorporated after nucleic acid synthesis, with the 5′ phosphate and 3′ hydroxyl providing convenient sites for post-synthetic covalent attachment of detectable labels.

[0137] Other post-synthetic approaches also permit internal labeling of nucleic acids. For example, fluorophores can be attached using a cisplatin reagent that reacts with the N7 of guanine residues (and, to a lesser extent, adenine bases) in DNA, RNA, and PNA to provide a stable coordination complex between the nucleic acid and fluorophore label (Universal Linkage System) (available from Molecular Probes, Inc., Eugene, Oreg., USA and Amersham Pharmacia Biotech, Piscataway, N.J., USA); see Alers et al., Genes, Chromosomes & Cancer 25: 301-305 (1999); Jelsma et al., J. NIH Res. 5: 82 (1994); Van Belkum et al., BioTechniques 16: 148-153 (1994), incorporated herein by reference. As another example, nucleic acids can be labeled using a disulfide-containing linker (FastTag™ Reagent, Vector Laboratories, Inc., Burlingame, Calif., USA) that is photo- or thermally-coupled to the target nucleic acid using aryl azide chemistry; after reduction, a free thiol is available for coupling to a hapten, fluorophore, sugar, affinity ligand, or other marker.

[0138] One or more independent or interacting labels can be incorporated into the nucleic acid molecules of the present invention. For example, both a fluorophore and a moiety that in proximity thereto acts to quench fluorescence can be included to report specific hybridization through release of fluorescence quenching or to report exonucleotidic excision. See, e.g., Tyagi et al., Nature Biotechnol. 14: 303-308 (1996); Tyagi et al., Nature Biotechnol. 16: 49-53 (1998); Sokol et al., Proc. Natl. Acad. Sci. USA 95: 11538-11543 (1998); Kostrikis et al., Science 279: 1228-1229 (1998); Marras et al., Genet. Anal. 14: 151-156 (1999); U.S. Pat. Nos. 5,846,726; 5,925,517; 5,925,517; 5,723,591 and 5,538,848; Holland et al., Proc. Natl. Acad. Sci. USA 88: 7276-7280 (1991); Heid et al., Genome Res. 6(10): 986-94 (1996); Kuimelis et al., Nucleic Acids Symp. Ser. (37): 255-6 (1997); the disclosures of which are incorporated herein by reference in their entireties.

[0139] Nucleic acid molecules of the invention may be modified by altering one or more native phosphodiester internucleoside bonds to more nuclease-resistant, internucleoside bonds. See Hartmann et al. (eds.), Manual of Antisense Methodology: Perspectives in Antisense Science, Kluwer Law International (1999); Stein et al. (eds.), Applied Antisense Oligonucleotide Technology, Wiley-Liss (1998); Chadwick et al. (eds.), Oligonucleotides as Therapeutic Agents—Symposium No. 209, John Wiley & Son Ltd (1997); the disclosures of which are incorporated herein by reference in their entireties. Such altered internucleoside bonds are often desired for antisense techniques or for targeted gene correction. See Gamper et al., Nucl. Acids Res. 28(21): 4332-4339 (2000), the disclosure of which is incorporated herein by reference in its entirety.

[0140] Modified oligonucleotide backbones include, without limitation, phosphorothioates, chiral phosphorothioates, phosphorodithioates, phosphotriesters, aminoalkylphosphotriesters, methyl and other alkyl phosphonates including 3′-alkylene phosphonates and chiral phosphonates, phosphinates, phosphoramidates including 3′-amino phosphoramidate and aminoalkylphosphoramidates, thionophosphoramidates, thionoalkylphosphonates, thionoalkylphosphotriesters, and boranophosphates having normal 3′-5′ linkages, 2′-5′ linked analogs of these, and those having inverted polarity wherein the adjacent pairs of nucleoside units are linked 3′-5′ to 5′-3′ or 2′-5′ to 5′-2′. Representative United States patents that teach the preparation of the above phosphorus-containing linkages include, but are not limited to, U.S. Pat. Nos. 3,687,808; 4,469,863; 4,476,301; 5,023,243; 5,177,196; 5,188,897; 5,264,423; 5,276,019; 5,278,302; 5,286,717; 5,321,131; 5,399,676; 5,405,939; 5,453,496; 5,455,233; 5,466,677; 5,476,925; 5,519,126; 5,536,821; 5,541,306; 5,550,111; 5,563,253; 5,571,799; 5,587,361; and 5,625,050, the disclosures of which are incorporated herein by reference in their entireties. In a preferred embodiment, the modified internucleoside linkages may be used for antisense techniques.

[0141] Other modified oligonucleotide backbones do not include a phosphorus atom, but have backbones that are formed by short chain alkyl or cycloalkyl internucleoside linkages, mixed heteroatom and alkyl or cycloalkyl internucleoside linkages, or one or more short chain heteroatomic or heterocyclic internucleoside linkages. These include those having morpholino linkages (formed in part from the sugar portion of a nucleoside); siloxane backbones; sulfide, sulfoxide and sulfone backbones; formacetyl and thioformacetyl backbones; methylene formacetyl and thioformacetyl backbones; alkene containing backbones; sulfamate backbones; methyleneimino and methylenehydrazino backbones; sulfonate and sulfonamide backbones; amide backbones; and others having mixed N, O, S and CH₂ component parts. Representative U.S. patents that teach the preparation of the above backbones include, but are not limited to, U.S. Pat. Nos. 5,034,506; 5,166,315; 5,185,444; 5,214,134; 5,216,141; 5,235,033; 5,264,562; 5,264,564; 5,405,938; 5,434,257; 5,466,677; 5,470,967; 5,489,677; 5,541,307; 5,561,225; 5,596,086; 5,602,240; 5,610,289; 5,602,240; 5,608,046; 5,610,289; 5,618,704; 5,623,070; 5,663,312; 5,633,360; 5,677,437 and 5,677,439; the disclosures of which are incorporated herein by reference in their entireties.

[0142] In other preferred oligonucleotide mimetics, both the sugar and the internucleoside linkage are replaced with novel groups, such as peptide nucleic acids (PNA). In PNA compounds, the phosphodiester backbone of the nucleic acid is replaced with an amide-containing backbone, in particular by repeating N-(2-aminoethyl) glycine units linked by amide bonds. Nucleobases are bound directly or indirectly to aza nitrogen atoms of the amide portion of the backbone, typically by methylene carbonyl linkages. PNA can be synthesized using a modified peptide synthesis protocol. PNA oligomers can be synthesized by both Fmoc and tBoc methods. Representative U.S. patents that teach the preparation of PNA compounds include, but are not limited to, U.S Pat. Nos. 5,539,082; 5,714,331; and 5,719,262, each of which is herein incorporated by reference. Automated PNA synthesis is readily achievable on commercial synthesizers (see, e.g., “PNA User's Guide,” Rev. 2, February 1998, Perseptive Biosystems Part No. 60138, Applied Biosystems, Inc., Foster City, Calif.).

[0143] PNA molecules are advantageous for a number of reasons. First, because the PNA backbone is uncharged, PNA/DNA and PNA/RNA duplexes have a higher thermal stability than is found in DNA/DNA and DNA/RNA duplexes. The Tm of a PNA/DNA or PNAIRNA duplex is generally 1° C. higher per base pair than the Tm of the corresponding DNA/DNA or DNA/RNA duplex (in 100 mM NaCl). Second, PNA molecules can also form stable PNA/DNA complexes at low ionic strength, under conditions in which DNA/DNA duplex formation does not occur. Third, PNA also demonstrates greater specificity in binding to complementary DNA because a PNA/DNA mismatch is more destabilizing than DNA/DNA mismatch. A single mismatch in mixed a PNA/DNA 15-mer lowers the Tm by 8-20° C. (15° C. on average). In the corresponding DNA/DNA duplexes, a single mismatch lowers the Tm by 4-16° C. (11° C. on average). Because PNA probes can be significantly shorter than DNA probes, their specificity is greater. Fourth, PNA oligomers are resistant to degradation by enzymes, and the lifetime of these compounds is extended both in vivo and in vitro because nucleases and proteases do not recognize the PNA polyamide backbone with nucleobase sidechains. See, e.g., Ray et al., FASEB J. 14(9): 1041-60 (2000); Nielsen et al., Pharmacol Toxicol. 86(1): 3-7 (2000); Larsen et al., Biochim Biophys Acta. 1489(1): 159-66 (1999); Nielsen, Curr. Opin. Struct. Biol. 9(3): 353-7 (1999), and Nielsen, Curr. Opin. Biotechnol. 10(1): 71-5 (1999), the disclosures of which are incorporated herein by reference in their entireties.

[0144] Nucleic acid molecules may be modified compared to their native structure throughout the length of the nucleic acid molecule or can be localized to discrete portions thereof. As an example of the latter, chimeric nucleic acids can be synthesized that have discrete DNA and RNA domains and that can be used for targeted gene repair and modified PCR reactions, as further described in U.S. Pat. Nos. 5,760,012 and 5,731,181, Misra et al., Biochem. 37: 1917-1925 (1998); and Finn et al., Nucl. Acids Res. 24: 3357-3363 (1996), the disclosures of which are incorporated herein by reference in their entireties.

[0145] Unless otherwise specified, nucleic acids of the present invention can include any topological conformation appropriate to the desired use; the term thus explicitly comprehends, among others, single-stranded, double-stranded, triplexed, quadruplexed, partially double-stranded, partially-triplexed, partially-quadruplexed, branched, hairpinned, circular, and padlocked conformations. Padlock conformations and their utilities are further described in Banér et al., Curr. Opin. Biotechnol. 12: 11-15 (2001); Escude et al., Proc. Natl. Acad. Sci. USA 14: 96(19):10603-7 (1999); Nilsson et al., Science 265(5181): 2085-8 (1994), the disclosures of which are incorporated herein by reference in their entireties. Triplex and quadruplex conformations, and their utilities, are reviewed in Praseuth et al., Biochim. Biophys. Acta. 1489(1): 181-206 (1999); Fox, Curr. Med. Chem. 7(1): 17-37 (2000); Kochetkova et al., Methods Mol. Biol. 130: 189-201 (2000); Chan et al., J. Mol. Med. 75(4): 267-82 (1997), the disclosures of which are incorporated herein by reference in their entireties.

[0146] Methods for Using Nucleic Acid Molecules as Probes and Primers

[0147] The isolated nucleic acid molecules of the present invention can be used as hybridization probes to detect, characterize, and quantify hybridizing nucleic acids in, and isolate hybridizing nucleic acids from, both genomic and transcript-derived nucleic acid samples. When free in solution, such probes are typically, but not invariably, detectably labeled; bound to a substrate, as in a microarray, such probes are typically, but not invariably unlabeled.

[0148] In one embodiment, the isolated nucleic acids of the present invention can be used as probes to detect and characterize gross alterations in the gene of a BSNA, such as deletions, insertions, translocations, and duplications of the BSNA genomic locus through fluorescence in situ hybridization (FISH) to chromosome spreads. See, e.g., Andreeff et al. (eds.), Introduction to Fluorescence In Situ Hybridization: Principles and Clinical Applications, John Wiley & Sons (1999), the disclosure of which is incorporated herein by reference in its entirety. The isolated nucleic acids of the present invention can be used as probes to assess smaller genomic alterations using, e.g., Southern blot detection of restriction fragment length polymorphisms. The isolated nucleic acid molecules of the present invention can be used as probes to isolate genomic clones that include the nucleic acid molecules of the present invention, which thereafter can be restriction mapped and sequenced to identify deletions, insertions, translocations, and substitutions (single nucleotide polymorphisms, SNPs) at the sequence level.

[0149] In another embodiment, the isolated nucleic acid molecules of the present invention can be used as probes to detect, characterize, and quantify BSNA in, and isolate BSNA from, transcript-derived nucleic acid samples. In one aspect, the isolated nucleic acid molecules of the present invention can be used as hybridization probes to detect, characterize by length, and quantify mRNA by Northern blot of total or poly-A⁺-selected RNA samples. In another aspect, the isolated nucleic acid molecules of the present invention can be used as hybridization probes to detect, characterize by location, and quantify mRNA by in situ hybridization to tissue sections. See, e.g., Schwarchzacher et al., In Situ Hybridization, Springer-Verlag New York (2000), the disclosure of which is incorporated herein by reference in its entirety. In another preferred embodiment, the isolated nucleic acid molecules of the present invention can be used as hybridization probes to measure the representation of clones in a cDNA library or to isolate hybridizing nucleic acid molecules acids from cDNA libraries, permitting sequence level characterization of mRNAs that hybridize to BSNAs, including, without limitations, identification of deletions, insertions, substitutions, truncations, alternatively spliced forms and single nucleotide polymorphisms. In yet another preferred embodiment, the nucleic acid molecules of the instant invention may be used in microarrays.

[0150] All of the aforementioned probe techniques are well within the skill in the art, and are described at greater length in standard texts such as Sambrook (2001), supra; Ausubel (1999), supra; and Walker et al. (eds.), The Nucleic Acids Protocols Handbook, Humana Press (2000), the disclosures of which are incorporated herein by reference in their entirety.

[0151] Thus, in one embodiment, a nucleic acid molecule of the invention may be used as a probe or primer to identify or amplify a second nucleic acid molecule that selectively hybridizes to the nucleic acid molecule of the invention. In a preferred embodiment, the probe or primer is derived from a nucleic acid molecule encoding a BSP. In a more preferred embodiment, the probe or primer is derived from a nucleic acid molecule encoding a polypeptide having an amino acid sequence of SEQ ID NO: 172 through 295. In another preferred embodiment, the probe or primer is derived from a BSNA. In a more preferred embodiment, the probe or primer is derived from a nucleic acid molecule having a nucleotide sequence of SEQ ID NO: 1 through 171.

[0152] In general, a probe or primer is at least 10 nucleotides in length, more preferably at least 12, more preferably at least 14 and even more preferably at least 16 or 17 nucleotides in length. In an even more preferred embodiment, the probe or primer is at least 18 nucleotides in length, even more preferably at least 20 nucleotides and even more preferably at least 22 nucleotides in length. Primers and probes may also be longer in length. For instance, a probe or primer may be 25 nucleotides in length, or may be 30, 40 or 50 nucleotides in length. Methods of performing nucleic acid hybridization using oligonucleotide probes are well-known in the art. See, e.g., Sambrook et al., 1989, supra, Chapter 11 and pp. 11.31-11.32 and 11.40-11.44, which describes radiolabeling of short probes, and pp. 11.45-11.53, which describe hybridization conditions for oligonucleotide probes, including specific conditions for probe hybridization (pp. 11.50-11.51).

[0153] Methods of performing primer-directed amplification are also well-known in the art. Methods for performing the polymerase chain reaction (PCR) are compiled, inter alia, in McPherson, PCR Basics: From Background to Bench, Springer Verlag (2000); Innis et al. (eds.), PCR Applications: Protocols for Functional Genomics, Academic Press (1999); Gelfand et al. (eds.), PCR Strategies, Academic Press (1998); Newton et al., PCR, Springer-Verlag New York (1997); Burke (ed.), PCR: Essential Techniques, John Wiley & Son Ltd (1996); White (ed.), PCR Cloning Protocols: From Molecular Cloning to Genetic Engineering, Vol. 67, Humana Press (1996); McPherson et al. (eds.), PCR 2: A Practical Approach, Oxford University Press, Inc. (1995); the disclosures of which are incorporated herein by reference in their entireties. Methods for performing RT-PCR are collected, e.g., in Siebert et al. (eds.), Gene Cloning and Analysis by RT-PCR, Eaton Publishing Company/Bio Techniques Books Division, 1998; Siebert (ed.), PCR Technique:RT-PCR, Eaton Publishing Company/BioTechniques Books (1995); the disclosure of which is incorporated herein by reference in its entirety.

[0154] PCR and hybridization methods may be used to identify and/or isolate allelic variants, homologous nucleic acid molecules and fragments of the nucleic acid molecules of the invention. PCR and hybridization methods may also be used to identify, amplify and/or isolate nucleic acid molecules that encode homologous proteins, analogs, fusion protein or muteins of the invention. The nucleic acid primers of the present invention can be used to prime amplification of nucleic acid molecules of the invention, using transcript-derived or genomic DNA as template.

[0155] The nucleic acid primers of the present invention can also be used, for example, to prime single base extension (SBE) for SNP detection (See, e.g., U.S. Pat. No. 6,004,744, the disclosure of which is incorporated herein by reference in its entirety).

[0156] Isothermal amplification approaches, such as rolling circle amplification, are also now well-described. See, e.g., Schweitzer et al., Curr. Opin. Biotechnol. 12(1): 21-7 (2001); U.S. Pat. Nos. 5,854,033 and 5,714,320; and international patent publications WO 97/19193 and WO 00/15779, the disclosures of which are incorporated herein by reference in their entireties. Rolling circle amplification can be combined with other techniques to facilitate SNP detection. See, e.g., Lizardi et al., Nature Genet. 19(3): 225-32 (1998).

[0157] Nucleic acid molecules of the present invention may be bound to a substrate either covalently or noncovalently. The substrate can be porous or solid, planar or non-planar, unitary or distributed. The bound nucleic acid molecules may be used as hybridization probes, and may be labeled or unlabeled. In a preferred embodiment, the bound nucleic acid molecules are unlabeled.

[0158] In one embodiment, the nucleic acid molecule of the present invention is bound to a porous substrate, e.g., a membrane, typically comprising nitrocellulose, nylon, or positively-charged derivatized nylon. The nucleic acid molecule of the present invention can be used to detect a hybridizing nucleic acid molecule that is present within a labeled nucleic acid sample, e.g., a sample of transcript-derived nucleic acids. In another embodiment, the nucleic acid molecule is bound to a solid substrate, including, without limitation, glass, amorphous silicon, crystalline silicon or plastics. Examples of plastics include, without limitation, polymethylacrylic, polyethylene, polypropylene, polyacrylate, polymethylmethacrylate, polyvinylchloride, polytetrafluoroethylene, polystyrene, polycarbonate, polyacetal, polysulfone, celluloseacetate, cellulosenitrate, nitrocellulose, or mixtures thereof. The solid substrate may be any shape, including rectangular, disk-like and spherical. In a preferred embodiment, the solid substrate is a microscope slide or slide-shaped substrate.

[0159] The nucleic acid molecule of the present invention can be attached covalently to a surface of the support substrate or applied to a derivatized surface in a chaotropic agent that facilitates denaturation and adherence by presumed noncovalent interactions, or some combination thereof. The nucleic acid molecule of the present invention can be bound to a substrate to which a plurality of other nucleic acids are concurrently bound, hybridization to each of the plurality of bound nucleic acids being separately detectable. At low density, e.g. on a porous membrane, these substrate-bound collections are typically denominated macroarrays; at higher density, typically on a solid support, such as glass, these substrate bound collections of plural nucleic acids are colloquially termed microarrays. As used herein, the term microarray includes arrays of all densities. It is, therefore, another aspect of the invention to provide microarrays that include the nucleic acids of the present invention.

[0160] Expression Vectors, Host Cells and Recombinant Methods of Producing Polypeptides

[0161] Another aspect of the present invention relates to vectors that comprise one or more of the isolated nucleic acid molecules of the present invention, and host cells in which such vectors have been introduced.

[0162] The vectors can be used, inter alia, for propagating the nucleic acids of the present invention in host cells (cloning vectors), for shuttling the nucleic acids of the present invention between host cells derived from disparate organisms (shuttle vectors), for inserting the nucleic acids of the present invention into host cell chromosomes (insertion vectors), for expressing sense or antisense RNA transcripts of the nucleic acids of the present invention in vitro or within a host cell, and for expressing polypeptides encoded by the nucleic acids of the present invention, alone or as fusions to heterologous polypeptides (expression vectors). Vectors of the present invention will often be suitable for several such uses.

[0163] Vectors are by now well-known in the art, and are described, inter alia, in Jones et al. (eds.), Vectors: Cloning Applications: Essential Techniques (Essential Techniques Series), John Wiley & Son Ltd. (1998); Jones et al. (eds.), Vectors: Expression Systems: Essential Techniques (Essential Techniques Series), John Wiley & Son Ltd. (1998); Gacesa et al., Vectors: Essential Data, John Wiley & Sons Ltd. (1995); Cid-Arregui (eds.), Viral Vectors: Basic Science and Gene Therapy, Eaton Publishing Co. (2000); Sambrook (2001), supra; Ausubel (1999), supra; the disclosures of which are incorporated herein by reference in their entireties. Furthermore, an enormous variety of vectors are available commercially. Use of existing vectors and modifications thereof being well within the skill in the art, only basic features need be described here.

[0164] Nucleic acid sequences may be expressed by operatively linking them to an expression control sequence in an appropriate expression vector and employing that expression vector to transform an appropriate unicellular host. Expression control sequences are sequences which control the transcription, post-transcriptional events and translation of nucleic acid sequences. Such operative linking of a nucleic sequence of this invention to an expression control sequence, of course, includes, if not already part of the nucleic acid sequence, the provision of a translation initiation codon, ATG or GTG, in the correct reading frame upstream of the nucleic acid sequence.

[0165] A wide variety of host/expression vector combinations may be employed in expressing the nucleic acid sequences of this invention. Useful expression vectors, for example, may consist of segments of chromosomal, non-chromosomal and synthetic nucleic acid sequences.

[0166] In one embodiment, prokaryotic cells may be used with an appropriate vector. Prokaryotic host cells are often used for cloning and expression. In a preferred embodiment, prokaryotic host cells include E. coli, Pseudomonas, Bacillus and Streptomyces. In a preferred embodiment, bacterial host cells are used to express the nucleic acid molecules of the instant invention. Useful expression vectors for bacterial hosts include bacterial plasmids, such as those from E. coli, Bacillus or Streptomyces, including pBluescript, pGEX-2T, pUC vectors, col E1, pCR1, pBR322, pMB9 and their derivatives, wider host range plasmids, such as RP4, phage DNAs, e.g., the numerous derivatives of phage lambda, e.g., NM989, λGT10 and λGT11, and other phages, e.g., M13 and filamentous single-stranded phage DNA. Where E. coli is used as host, selectable markers are, analogously, chosen for selectivity in gram negative bacteria: e.g., typical markers confer resistance to antibiotics, such as ampicillin, tetracycline, chloramphenicol, kanamycin, streptomycin and zeocin; auxotrophic markers can also be used.

[0167] In other embodiments, eukaryotic host cells, such as yeast, insect, mammalian or plant cells, may be used. Yeast cells, typically S. cerevisiae, are useful for eukaryotic genetic studies, due to the ease of targeting genetic changes by homologous recombination and the ability to easily complement genetic defects using recombinantly expressed proteins. Yeast cells are useful for identifying interacting protein components, e.g. through use of a two-hybrid system. In a preferred embodiment, yeast cells are useful for protein expression. Vectors of the present invention for use in yeast will typically, but not invariably, contain an origin of replication suitable for use in yeast and a selectable marker that is functional in yeast. Yeast vectors include Yeast Integrating plasmids (e.g., YIp5) and Yeast Replicating plasmids (the YRp and YEp series plasmids), Yeast Centromere plasmids (the YCp series plasmids), Yeast Artificial Chromosomes (YACs) which are based on yeast linear plasmids, denoted YLp, pGPD-2, 2μ plasmids and derivatives thereof, and improved shuttle vectors such as those described in Gietz et al., Gene, 74: 527-34 (1988) (YIplac, YEplac and YCplac). Selectable markers in yeast vectors include a variety of auxotrophic markers, the most common of which are (in Saccharomyces cerevisiae) URA3, HIS3, LEU2, TRP1 and LYS2, which complement specific auxotrophic mutations, such as ura3-52, his3-D1, leu2-D1, trp1-D1 and lys2-201.

[0168] Insect cells are often chosen for high efficiency protein expression. Where the host cells are from Spodoptera frugiperda, e.g., Sf9 and Sf21 cell lines, and expresSF™ cells (Protein Sciences Corp., Meriden, Conn., USA)), the vector replicative strategy is typically based upon the baculovirus life cycle. Typically, baculovirus transfer vectors are used to replace the wild-type AcMNPV polyhedrin gene with a heterologous gene of interest. Sequences that flank the polyhedrin gene in the wild-type genome are positioned 5′ and 3′ of the expression cassette on the transfer vectors. Following co-transfection with AcMNPV DNA, a homologous recombination event occurs between these sequences resulting in a recombinant virus carrying the gene of interest and the polyhedrin or p10 promoter. Selection can be based upon visual screening for lacZ fusion activity.

[0169] In another embodiment, the host cells may be mammalian cells, which are particularly useful for expression of proteins intended as pharmaceutical agents, and for screening of potential agonists and antagonists of a protein or a physiological pathway. Mammalian vectors intended for autonomous extrachromosomal replication will typically include a viral origin, such as the SV40 origin (for replication in cell lines expressing the large T-antigen, such as COS1 and COS7 cells), the papillomavirus origin, or the EBV origin for long term episomal replication (for use, e.g., in 293-EBNA cells, which constitutively express the EBV EBNA-1 gene product and adenovirus E1A). Vectors intended for integration, and thus replication as part of the mammalian chromosome, can, but need not, include an origin of replication functional in mammalian cells, such as the SV40 origin. Vectors based upon viruses, such as adenovirus, adeno-associated virus, vaccinia virus, and various mammalian retroviruses, will typically replicate according to the viral replicative strategy. Selectable markers for use in mammalian cells include resistance to neomycin (G418), blasticidin, hygromycin and to zeocin, and selection based upon the purine salvage pathway using HAT medium.

[0170] Expression in mammalian cells can be achieved using a variety of plasmids, including pSV2, pBC12BI, and p91023, as well as lytic virus vectors (e.g., vaccinia virus, adeno virus, and baculovirus), episomal virus vectors (e.g., bovine papillomavirus), and retroviral vectors (e.g., murine retroviruses). Useful vectors for insect cells include baculoviral vectors and pVL 941.

[0171] Plant cells can also be used for expression, with the vector replicon typically derived from a plant virus (e.g., cauliflower mosaic virus, CaMV; tobacco mosaic virus, TMV) and selectable markers chosen for suitability in plants.

[0172] It is known that codon usage of different host cells may be different. For example, a plant cell and a human cell may exhibit a difference in codon preference for encoding a particular amino acid. As a result, human mRNA may not be efficiently translated in a plant, bacteria or insect host cell. Therefore, another embodiment of this invention is directed to codon optimization. The codons of the nucleic acid molecules of the invention may be modified to resemble, as much as possible, genes naturally contained within the host cell without altering the amino acid sequence encoded by the nucleic acid molecule.

[0173] Any of a wide variety of expression control sequences may be used in these vectors to express the DNA sequences of this invention. Such useful expression control sequences include the expression control sequences associated with structural genes of the foregoing expression vectors. Expression control sequences that control transcription include, e.g., promoters, enhancers and transcription termination sites. Expression control sequences in eukaryotic cells that control post-transcriptional events include splice donor and acceptor sites and sequences that modify the half-life of the transcribed RNA, e.g., sequences that direct poly(A) addition or binding sites for RNA-binding proteins. Expression control sequences that control translation include ribosome binding sites, sequences which direct targeted expression of the polypeptide to or within particular cellular compartments, and sequences in the 5′ and 3′ untranslated regions that modify the rate or efficiency of translation.

[0174] Examples of useful expression control sequences for a prokaryote, e.g., E. coli, will include a promoter, often a phage promoter, such as phage lambda pL promoter, the trc promoter, a hybrid derived from the trp and lac promoters, the bacteriophage T7 promoter (in E. coli cells engineered to express the T7 polymerase), the TAC or TRC system, the major operator and promoter regions of phage lambda, the control regions of fd coat protein, or the araBAD operon. Prokaryotic expression vectors may further include transcription terminators, such as the aspA terminator, and elements that facilitate translation, such as a consensus ribosome binding site and translation termination codon, Schomer et al., Proc. Natl. Acad. Sci. USA 83: 8506-8510 (1986).

[0175] Expression control sequences for yeast cells, typically S. cerevisiae, will include a yeast promoter, such as the CYC1 promoter, the GAL1 promoter, the GAL10 promoter, ADH1 promoter, the promoters of the yeast α-mating system, or the GPD promoter, and will typically have elements that facilitate transcription termination, such as the transcription termination signals from the CYC1 or ADH1 gene.

[0176] Expression vectors useful for expressing proteins in mammalian cells will include a promoter active in mammalian cells. These promoters include those derived from mammalian viruses, such as the enhancer-promoter sequences from the immediate early gene of the human cytomegalovirus (CMV), the enhancer-promoter sequences from the Rous sarcoma virus long terminal repeat (RSV LTR), the enhancer-promoter from SV40 or the early and late promoters of adenovirus. Other expression control sequences include the promoter for 3-phosphoglycerate kinase or other glycolytic enzymes, the promoters of acid phosphatase. Other expression control sequences include those from the gene comprising the BSNA of interest. Often, expression is enhanced by incorporation of polyadenylation sites, such as the late SV40 polyadenylation site and the polyadenylation signal and transcription termination sequences from the bovine growth hormone (BGH) gene, and ribosome binding sites. Furthermore, vectors can include introns, such as intron II of rabbit β-globin gene and the SV40 splice elements.

[0177] Preferred nucleic acid vectors also include a selectable or amplifiable marker gene and means for amplifying the copy number of the gene of interest. Such marker genes are well-known in the art. Nucleic acid vectors may also comprise stabilizing sequences (e.g., ori- or ARS-like sequences and telomere-like sequences), or may alternatively be designed to favor directed or non-directed integration into the host cell genome. In a preferred embodiment, nucleic acid sequences of this invention are inserted in frame into an expression vector that allows high level expression of an RNA which encodes a protein comprising the encoded nucleic acid sequence of interest. Nucleic acid cloning and sequencing methods are well-known to those of skill in the art and are described in an assortment of laboratory manuals, including Sambrook (1989), supra, Sambrook (2000), supra; and Ausubel (1992), supra, Ausubel (1999), supra. Product information from manufacturers of biological, chemical and immunological reagents also provide useful information.

[0178] Expression vectors may be either constitutive or inducible. Inducible vectors include either naturally inducible promoters, such as the trc promoter, which is regulated by the lac operon, and the pL promoter, which is regulated by tryptophan, the MMTV-LTR promoter, which is inducible by dexamethasone, or can contain synthetic promoters and/or additional elements that confer inducible control on adjacent promoters. Examples of inducible synthetic promoters are the hybrid Plac/ara-1 promoter and the PLtetO-1 promoter. The PltetO-1 promoter takes advantage of the high expression levels from the PL promoter of phage lambda, but replaces the lambda repressor sites with two copies of operator 2 of the Tn10 tetracycline resistance operon, causing this promoter to be tightly repressed by the Tet repressor protein and induced in response to tetracycline (Tc) and Tc derivatives such as anhydrotetracycline. Vectors may also be inducible because they contain hormone response elements, such as the glucocorticoid response element (GRE) and the estrogen response element (ERE), which can confer hormone inducibility where vectors are used for expression in cells having the respective hormone receptors. To reduce background levels of expression, elements responsive to ecdysone, an insect hormone, can be used instead, with coexpression of the ecdysone receptor.

[0179] In one aspect of the invention, expression vectors can be designed to fuse the expressed polypeptide to small protein tags that facilitate purification and/or visualization. Tags that facilitate purification include a polyhistidine tag that facilitates purification of the fusion protein by immobilized metal affinity chromatography, for example using NiNTA resin (Qiagen Inc., Valencia, Calif., USA) or TALON™ resin (cobalt immobilized affinity chromatography medium, Clontech Labs, Palo Alto, Calif., USA). The fusion protein can include a chitin-binding tag and self-excising intein, permitting chitin-based purification with self-removal of the fused tag (IMPACT™ system, New England Biolabs, Inc., Beverley, Mass., USA). Alternatively, the fusion protein can include a calmodulin-binding peptide tag, permitting purification by calmodulin affinity resin (Stratagene, La Jolla, Calif., USA), or a specifically excisable fragment of the biotin carboxylase carrier protein, permitting purification of in vivo biotinylated protein using an avidin resin and subsequent tag removal (Promega, Madison, Wis., USA). As another useful alternative, the proteins of the present invention can be expressed as a fusion protein with glutathione-S-transferase, the affinity and specificity of binding to glutathione permitting purification using glutathione affinity resins, such as Glutathione-Superflow Resin (Clontech Laboratories, Palo Alto, Calif., USA), with subsequent elution with free glutathione. Other tags include, for example, the Xpress epitope, detectable by anti-Xpress antibody (Invitrogen, Carlsbad, Calif., USA), a myc tag, detectable by anti-myc tag antibody, the V5 epitope, detectable by anti-V5 antibody (Invitrogen, Carlsbad, Calif., USA), FLAG® epitope, detectable by anti-FLAG® antibody (Stratagene, La Jolla, Calif., USA), and the HA epitope.

[0180] For secretion of expressed proteins, vectors can include appropriate sequences that encode secretion signals, such as leader peptides. For example, the pSecTag2 vectors (Invitrogen, Carlsbad, Calif., USA) are 5.2 kb mammalian expression vectors that carry the secretion signal from the V-J2-C region of the mouse Ig kappa-chain for efficient secretion of recombinant proteins from a variety of mammalian cell lines.

[0181] Expression vectors can also be designed to fuse proteins encoded by the heterologous nucleic acid insert to polypeptides that are larger than purification and/or identification tags. Useful fusion proteins include those that permit display of the encoded protein on the surface of a phage or cell, fusion to intrinsically fluorescent proteins, such as those that have a green fluorescent protein (GFP)-like chromophore, fusions to the IgG Fc region, and fusion proteins for use in two hybrid systems.

[0182] Vectors for phage display fuse the encoded polypeptide to, e.g., the gene III protein (pIII) or gene VIII protein (pVIII) for display on the surface of filamentous phage, such as M13. See Barbas et al., Phage Display: A Laboratory Manual, Cold Spring Harbor Laboratory Press (2001); Kay et al. (eds.), Phage Display of Peptides and Proteins: A Laboratory Manual, Academic Press, Inc., (1996); Abelson et al. (eds.), Combinatorial Chemistry (Methods in Enzymology, Vol. 267) Academic Press (1996). Vectors for yeast display, e.g. the pYD1 yeast display vector (Invitrogen, Carlsbad, Calif., USA), use the (α-agglutinin yeast adhesion receptor to display recombinant protein on the surface of S. cerevisiae. Vectors for mammalian display, e.g., the pDisplay™ vector (Invitrogen, Carlsbad, Calif., USA), target recombinant proteins using an N-terminal cell surface targeting signal and a C-terminal transmembrane anchoring domain of platelet derived growth factor receptor.

[0183] A wide variety of vectors now exist that fuse proteins encoded by heterologous nucleic acids to the chromophore of the substrate-independent, intrinsically fluorescent green fluorescent protein from Aequorea victoria (“GFP”) and its variants. The GFP-like chromophore can be selected from GFP-like chromophores found in naturally occurring proteins, such as A. victoria GFP (GenBank accession number AAA27721), Renilla reniformis GFP, FP583 (GenBank accession no. AF168419) (DsRed), FP593 (AF272711), FP483 (AF168420), FP484 (AF168424), FP595 (AF246709), FP486 (AF168421), FP538 (AF168423), and FP506 (AF168422), and need include only so much of the native protein as is needed to retain the chromophore's intrinsic fluorescence. Methods for determining the minimal domain required for fluorescence are known in the art. See Li et al., J. Biol. Chem. 272: 28545-28549 (1997). Alternatively, the GFP-like chromophore can be selected from GFP-like chromophores modified from those found in nature. The methods for engineering such modified GFP-like chromophores and testing them for fluorescence activity, both alone and as part of protein fusions, are well-known in the art. See Heim et al., Curr. Biol. 6: 178-182 (1996) and Palm et al., Methods Enzymol. 302: 378-394 (1999), incorporated herein by reference in its entirety. A variety of such modified chromophores are now commercially available and can readily be used in the fusion proteins of the present invention. These include EGFP (“enhanced GFP”), EBFP (“enhanced blue fluorescent protein”), BFP2, EYFP (“enhanced yellow fluorescent protein”), ECFP (“enhanced cyan fluorescent protein”) or Citrine. EGFP (see, e.g, Cormack et al., Gene 173: 33-38 (1996); U.S. Pat. Nos. 6,090,919 and 5,804,387) is found on a variety of vectors, both plasmid and viral, which are available commercially (Clontech Labs, Palo Alto, Calif., USA); EBFP is optimized for expression in mammalian cells whereas BFP2, which retains the original jellyfish codons, can be expressed in bacteria (see, e.g,. Heim et al., Curr. Biol. 6: 178-182 (1996) and Cormack et al., Gene 173: 33-38 (1996)). Vectors containing these blue-shifted variants are available from Clontech Labs (Palo Alto, Calif., USA). Vectors containing EYFP, ECFP (see, e.g., Heim et al., Curr. Biol. 6: 178-182 (1996); Miyawaki et al., Nature 388: 882-887 (1997)) and Citrine (see, e.g., Heikal et al., Proc. Natl. Acad. Sci. USA 97: 11996-12001 (2000)) are also available from Clontech Labs. The GFP-like chromophore can also be drawn from other modified GFPs, including those described in U.S. Pat. Nos. 6,124,128; 6,096,865; 6,090,919; 6,066,476; 6,054,321; 6,027,881; 5,968,750; 5,874,304; 5,804,387; 5,777,079; 5,741,668; and 5,625,048, the disclosures of which are incorporated herein by reference in their entireties. See also Conn (ed.), Green Fluorescent Protein (Methods in Enzymology, Vol. 302), Academic Press, Inc. (1999). The GFP-like chromophore of each of these GFP variants can usefully be included in the fusion proteins of the present invention.

[0184] Fusions to the IgG Fc region increase serum half life of protein pharmaceutical products through interaction with the FcRn receptor (also denominated the FcRp receptor and the Brambell receptor, FcRb), further described in International Patent Application Nos. WO 97/43316, WO 97/34631, WO 96/32478, WO 96/18412.

[0185] For long-term, high-yield recombinant production of the proteins, protein fusions, and protein fragments of the present invention, stable expression is preferred. Stable expression is readily achieved by integration into the host cell genome of vectors having selectable markers, followed by selection of these integrants. Vectors such as pUB6/V5-His A, B, and C (Invitrogen, Carlsbad, Calif., USA) are designed for high-level stable expression of heterologous proteins in a wide range of mammalian tissue types and cell lines. pUB6/V5-His uses the promoter/enhancer sequence from the human ubiquitin C gene to drive expression of recombinant proteins: expression levels in 293, CHO, and NIH3T3 cells are comparable to levels from the CMV and human EF-1a promoters. The bsd gene permits rapid selection of stably transfected mammalian cells with the potent antibiotic blasticidin.

[0186] Replication incompetent retroviral vectors, typically derived from Moloney murine leukemia virus, also are useful for creating stable transfectants having integrated provirus. The highly efficient transduction machinery of retroviruses, coupled with the availability of a variety of packaging cell lines such as RetroPack™ PT 67, EcoPack2™-293, AmphoPack-293, and GP2-293 cell lines (all available from Clontech Laboratories, Palo Alto, Calif., USA), allow a wide host range to be infected with high efficiency; varying the multiplicity of infection readily adjusts the copy number of the integrated provirus.

[0187] Of course, not all vectors and expression control sequences will function equally well to express the nucleic acid sequences of this invention. Neither will all hosts function equally well with the same expression system. However, one of skill in the art may make a selection among these vectors, expression control sequences and hosts without undue experimentation and without departing from the scope of this invention. For example, in selecting a vector, the host must be considered because the vector must be replicated in it. The vector's copy number, the ability to control that copy number, the ability to control integration, if any, and the expression of any other proteins encoded by the vector, such as antibiotic or other selection markers, should also be considered. The present invention further includes host cells comprising the vectors of the present invention, either present episomally within the cell or integrated, in whole or in part, into the host cell chromosome. Among other considerations, some of which are described above, a host cell strain may be chosen for its ability to process the expressed protein in the desired fashion. Such post-translational modifications of the polypeptide include, but are not limited to, acetylation, carboxylation, glycosylation, phosphorylation, lipidation, and acylation, and it is an aspect of the present invention to provide BSPs with such post-translational modifications.

[0188] Polypeptides of the invention may be post-translationally modified. Post-translational modifications include phosphorylation of amino acid residues serine, threonine and/or tyrosine, N-linked and/or O-linked glycosylation, methylation, acetylation, prenylation, methylation, acetylation, arginylation, ubiquination and racemization. One may determine whether a polypeptide of the invention is likely to be post-translationally modified by analyzing the sequence of the polypeptide to determine if there are peptide motifs indicative of sites for post-translational modification. There are a number of computer programs that permit prediction of post-translational modifications. See, e.g., www.expasy.org (accessed Aug. 31, 2001), which includes PSORT, for prediction of protein sorting signals and localization sites, SignalP, for prediction of signal peptide cleavage sites, MITOPROT and Predotar, for prediction of mitochondrial targeting sequences, NetOGlyc, for prediction of type O-glycosylation sites in mammalian proteins, big-PI Predictor and DGPI, for prediction of prenylation-anchor and cleavage sites, and NetPhos, for prediction of Ser, Thr and Tyr phosphorylation sites in eukaryotic proteins. Other computer programs, such as those included in GCG, also may be used to determine post-translational modification peptide motifs.

[0189] General examples of types of post-translational modifications may be found in web sites such as the Delta Mass database http://www.abrf.org/ABRF/Research Committees/deltamass/deltamass.html (accessed Oct. 19, 2001); “GlycoSuiteDB: a new curated relational database of glycoprotein glycan structures and their biological sources” Cooper et al. Nucleic Acids Res. 29; 332-335 (2001) and http://www.glycosuite.com/(accessed Oct. 19, 2001); “O-GLYCBASE version 4.0: a revised database of O-glycosylated proteins” Gupta et al. Nucleic Acids Research, 27: 370-372 (1999) and http://www.cbs.dtu.dk/databases/OGLYCBASE/(accessed Oct. 19, 2001); “PhosphoBase, a database of phosphorylation sites: release 2.0.”, Kreegipuu et al. Nucleic Acids Res 27(1):237-239 (1999) and http://www.cbs.dtu.dk/databases/PhosphoBase/(accessed Oct. 19, 2001); or http://pir.georgetown.edu/pirwww/search/textresid.html (accessed Oct. 19, 2001).

[0190] Tumorigenesis is often accompanied by alterations in the post-translational modifications of proteins. Thus, in another embodiment, the invention provides polypeptides from cancerous cells or tissues that have altered post-translational modifications compared to the post-translational modifications of polypeptides from normal cells or tissues. A number of altered post-translational modifications are known. One common alteration is a change in phosphorylation state, wherein the polypeptide from the cancerous cell or tissue is hyperphosphorylated or hypophosphorylated compared to the polypeptide from a normal tissue, or wherein the polypeptide is phosphorylated on different residues than the polypeptide from a normal cell. Another common alteration is a change in glycosylation state, wherein the polypeptide from the cancerous cell or tissue has more or less glycosylation than the polypeptide from a normal tissue, and/or wherein the polypeptide from the cancerous cell or tissue has a different type of glycosylation than the polypeptide from a noncancerous cell or tissue. Changes in glycosylation may be critical because carbohydrate-protein and carbohydrate-carbohydrate interactions are important in cancer cell progression, dissemination and invasion. See, e.g., Barchi, Curr. Pharm. Des. 6: 485-501 (2000), Verma, Cancer Biochem. Biophys. 14: 151-162 (1994) and Dennis et al., Bioessays 5: 412-421 (1999).

[0191] Another post-translational modification that may be altered in cancer cells is prenylation. Prenylation is the covalent attachment of a hydrophobic prenyl group (either farnesyl or geranylgeranyl) to a polypeptide. Prenylation is required for localizing a protein to a cell membrane and is often required for polypeptide function. For instance, the Ras superfamily of GTPase signaling proteins must be prenylated for function in a cell. See, e.g., Prendergast et al., Semin. Cancer Biol. 10: 443-452 (2000) and Khwaja et al., Lancet 355: 741-744 (2000).

[0192] Other post-translation modifications that may be altered in cancer cells include, without limitation, polypeptide methylation, acetylation, arginylation or racemization of amino acid residues. In these cases, the polypeptide from the cancerous cell may exhibit either increased or decreased amounts of the post-translational modification compared to the corresponding polypeptides from noncancerous cells.

[0193] Other polypeptide alterations in cancer cells include abnormal polypeptide cleavage of proteins and aberrant protein-protein interactions. Abnormal polypeptide cleavage may be cleavage of a polypeptide in a cancerous cell that does not usually occur in a normal cell, or a lack of cleavage in a cancerous cell, wherein the polypeptide is cleaved in a normal cell. Aberrant protein-protein interactions may be either covalent cross-linking or non-covalent binding between proteins that do not normally bind to each other. Alternatively, in a cancerous cell, a protein may fail to bind to another protein to which it is bound in a noncancerous cell. Alterations in cleavage or in protein-protein interactions may be due to over- or underproduction of a polypeptide in a cancerous cell compared to that in a normal cell, or may be due to alterations in post-translational modifications (see above) of one or more proteins in the cancerous cell. See, e.g., Henschen-Edman, Ann. N.Y. Acad. Sci. 936: 580-593 (2001).

[0194] Alterations in polypeptide post-translational modifications, as well as changes in polypeptide cleavage and protein-protein interactions, may be determined by any method known in the art. For instance, alterations in phosphorylation may be determined by using anti-phosphoserine, anti-phosphothreonine or anti-phosphotyrosine antibodies or by amino acid analysis. Glycosylation alterations may be determined using antibodies specific for different sugar residues, by carbohydrate sequencing, or by alterations in the size of the glycoprotein, which can be determined by, e.g., SDS polyacrylamide gel electrophoresis (PAGE). Other alterations of post-translational modifications, such as prenylation, racemization, methylation, acetylation and arginylation, may be determined by chemical analysis, protein sequencing, amino acid analysis, or by using antibodies specific for the particular post-translational modifications. Changes in protein-protein interactions and in polypeptide cleavage may be analyzed by any method known in the art including, without limitation, non-denaturing PAGE (for non-covalent protein-protein interactions), SDS PAGE (for covalent protein-protein interactions and protein cleavage), chemical cleavage, protein sequencing or immunoassays.

[0195] In another embodiment, the invention provides polypeptides that have been post-translationally modified. In one embodiment, polypeptides may be modified enzymatically or chemically, by addition or removal of a post-translational modification. For example, a polypeptide may be glycosylated or deglycosylated enzymatically. Similarly, polypeptides may be phosphorylated using a purified kinase, such as a MAP kinase (e.g, p38, ERK, or JNK) or a tyrosine kinase (e.g., Src or erbB2). A polypeptide may also be modified through synthetic chemistry. Alternatively, one may isolate the polypeptide of interest from a cell or tissue that expresses the polypeptide with the desired post-translational modification. In another embodiment, a nucleic acid molecule encoding the polypeptide of interest is introduced into a host cell that is capable of post-translationally modifying the encoded polypeptide in the desired fashion. If the polypeptide does not contain a motif for a desired post-translational modification, one may alter the post-translational modification by mutating the nucleic acid sequence of a nucleic acid molecule encoding the polypeptide so that it contains a site for the desired post-translational modification. Amino acid sequences that may be post-translationally modified are known in the art. See, e.g., the programs described above on the website www.expasy.org. The nucleic acid molecule is then be introduced into a host cell that is capable of post-translationally modifying the encoded polypeptide. Similarly, one may delete sites that are post-translationally modified by either mutating the nucleic acid sequence so that the encoded polypeptide does not contain the post-translational modification motif, or by introducing the native nucleic acid molecule into a host cell that is not capable of post-translationally modifying the encoded polypeptide.

[0196] In selecting an expression control sequence, a variety of factors should also be considered. These include, for example, the relative strength of the sequence, its controllability, and its compatibility with the nucleic acid sequence of this invention, particularly with regard to potential secondary structures. Unicellular hosts should be selected by consideration of their compatibility with the chosen vector, the toxicity of the product coded for by the nucleic acid sequences of this invention, their secretion characteristics, their ability to fold the polypeptide correctly, their fermentation or culture requirements, and the ease of purification from them of the products coded for by the nucleic acid sequences of this invention.

[0197] The recombinant nucleic acid molecules and more particularly, the expression vectors of this invention may be used to express the polypeptides of this invention as recombinant polypeptides in a heterologous host cell. The polypeptides of this invention may be full-length or less than full-length polypeptide fragments recombinantly expressed from the nucleic acid sequences according to this invention. Such polypeptides include analogs, derivatives and muteins that may or may not have biological activity.

[0198] Vectors of the present invention will also often include elements that permit in vitro transcription of RNA from the inserted heterologous nucleic acid. Such vectors typically include a phage promoter, such as that from T7, T3, or SP6, flanking the nucleic acid insert. Often two different such promoters flank the inserted nucleic acid, permitting separate in vitro production of both sense and antisense strands.

[0199] Transformation and other methods of introducing nucleic acids into a host cell (e.g., conjugation, protoplast transformation or fusion, transfection, electroporation, liposome delivery, membrane fusion techniques, high velocity DNA-coated pellets, viral infection and protoplast fusion) can be accomplished by a variety of methods which are well-known in the art (See, for instance, Ausubel, supra, and Sambrook et al., supra). Bacterial, yeast, plant or mammalian cells are transformed or transfected with an expression vector, such as a plasmid, a cosmid, or the like, wherein the expression vector comprises the nucleic acid of interest. Alternatively, the cells may be infected by a viral expression vector comprising the nucleic acid of interest. Depending upon the host cell, vector, and method of transformation used, transient or stable expression of the polypeptide will be constitutive or inducible. One having ordinary skill in the art will be able to decide whether to express a polypeptide transiently or stably, and whether to express the protein constitutively or inducibly.

[0200] A wide variety of unicellular host cells are useful in expressing the DNA sequences of this invention. These hosts may include well-known eukaryotic and prokaryotic hosts, such as strains of, fungi, yeast, insect cells such as Spodoptera frugiperda (SF9), animal cells such as CHO, as well as plant cells in tissue culture. Representative examples of appropriate host cells include, but are not limited to, bacterial cells, such as E. coli, Caulobacter crescentus, Streptomyces species, and Salmonella typhimurium; yeast cells, such as Saccharomyces cerevisiae, Schizosaccharomyces pombe, Pichia pastoris, Pichia methanolica; insect cell lines, such as those from Spodoptera frugiperda, e.g., Sf9 and Sf21 cell lines, and expresSF™ cells (Protein Sciences Corp., Meriden, Conn., USA), Drosophila S2 cells, and Trichoplusia ni High Five® Cells (Invitrogen, Carlsbad, Calif., USA); and mammalian cells. Typical mammalian cells include BHK cells, BSC 1 cells, BSC 40 cells, BMT 10 cells, VERO cells, COS1 cells, COS7 cells, Chinese hamster ovary (CHO) cells, 3T3 cells, NIH 3T3 cells, 293 cells, HEPG2 cells, HeLa cells, L cells, MDCK cells, HEK293 cells, WI38 cells, murine ES cell lines (e.g., from strains 129/SV, C57/BL6, DBA-1, 129/SVJ), K562 cells, Jurkat cells, and BW5147 cells. Other mammalian cell lines are well-known and readily available from the American Type Culture Collection (ATCC) (Manassas, Va., USA) and the National Institute of General Medical Sciences (NIGMS) Human Genetic Cell Repository at the Coriell Cell Repositories (Camden, N.J., USA). Cells or cell lines derived from breast are particularly preferred because they may provide a more native post-translational processing. Particularly preferred are human breast cells.

[0201] Particular details of the transfection, expression and purification of recombinant proteins are well documented and are understood by those of skill in the art. Further details on the various technical aspects of each of the steps used in recombinant production of foreign genes in bacterial cell expression systems can be found in a number of texts and laboratory manuals in the art. See, e.g., Ausubel (1992), supra, Ausubel (1999), supra, Sambrook (1989), supra, and Sambrook (2001), supra, herein incorporated by reference.

[0202] Methods for introducing the vectors and nucleic acids of the present invention into the host cells are well-known in the art; the choice of technique will depend primarily upon the specific vector to be introduced and the host cell chosen.

[0203] Nucleic acid molecules and vectors may be introduced into prokaryotes, such as E. coli, in a number of ways. For instance, phage lambda vectors will typically be packaged using a packaging extract (e.g., Gigapack® packaging extract, Stratagene, La Jolla, Calif., USA), and the packaged virus used to infect E. coli.

[0204] Plasmid vectors will typically be introduced into chemically competent or electrocompetent bacterial cells. E. coli cells can be rendered chemically competent by treatment, e.g., with CaCl₂, or a solution of Mg²⁺, Mn²⁺, Ca²⁺, Rb⁺ or K⁺, dimethyl sulfoxide, dithiothreitol, and hexamine cobalt (III), Hanahan, J. Mol. Biol. 166(4):557-80 (1983), and vectors introduced by heat shock. A wide variety of chemically competent strains are also available commercially (e.g., Epicurian Coli® XL10-Gold® Ultracompetent Cells (Stratagene, La Jolla, Calif., USA); DH5α competent cells (Clontech Laboratories, Palo Alto, Calif., USA); and TOP10 Chemically Competent E. coli Kit (Invitrogen, Carlsbad, Calif., USA)). Bacterial cells can be rendered electrocompetent, that is, competent to take up exogenous DNA by electroporation, by various pre-pulse treatments; vectors are introduced by electroporation followed by subsequent outgrowth in selected media. An extensive series of protocols is provided online in Electroprotocols (BioRad, Richmond, Calif., USA) (http://www.biorad.com/LifeScience/pdf/New_Gene_Pulser.pdf).

[0205] Vectors can be introduced into yeast cells by spheroplasting, treatment with lithium salts, electroporation, or protoplast fusion. Spheroplasts are prepared by the action of hydrolytic enzymes such as snail-gut extract, usually denoted Glusulase, or Zymolyase, an enzyme from Arthrobacter luteus, to remove portions of the cell wall in the presence of osmotic stabilizers, typically 1 M sorbitol. DNA is added to the spheroplasts, and the mixture is co-precipitated with a solution of polyethylene glycol (PEG) and Ca²⁺. Subsequently, the cells are resuspended in a solution of sorbitol, mixed with molten agar and then layered on the surface of a selective plate containing sorbitol.

[0206] For lithium-mediated transformation, yeast cells are treated with lithium acetate, which apparently permeabilizes the cell wall, DNA is added and the cells are co-precipitated with PEG. The cells are exposed to a brief heat shock, washed free of PEG and lithium acetate, and subsequently spread on plates containing ordinary selective medium. Increased frequencies of transformation are obtained by using specially-prepared single-stranded carrier DNA and certain organic solvents. Schiestl et al., Curr. Genet. 16(5-6): 339-46 (1989).

[0207] For electroporation, freshly-grown yeast cultures are typically washed, suspended in an osmotic protectant, such as sorbitol, mixed with DNA, and the cell suspension pulsed in an electroporation device. Subsequently, the cells are spread on the surface of plates containing selective media. Becker et al., Methods Enzymol. 194: 182-187 (1991). The efficiency of transformation by electroporation can be increased over 100-fold by using PEG, single-stranded carrier DNA and cells that are in late log-phase of growth. Larger constructs, such as YACs, can be introduced by protoplast fusion.

[0208] Mammalian and insect cells can be directly infected by packaged viral vectors, or transfected by chemical or electrical means. For chemical transfection, DNA can be coprecipitated with CaPO₄ or introduced using liposomal and nonliposomal lipid-based agents. Commercial kits are available for CaPO₄ transfection (CalPhos™ Mammalian Transfection Kit, Clontech Laboratories, Palo Alto, Calif., USA), and lipid-mediated transfection can be practiced using commercial reagents, such as LIPOFECTAMINE198 2000, LIPOFECTAMINE™ Reagent, CELLFECTIN® Reagent, and LIPOFECTIN® Reagent (Invitrogen, Carlsbad, Calif., USA), DOTAP Liposomal Transfection Reagent, FuGENE 6, X-tremeGENE Q2, DOSPER, (Roche Molecular Biochemicals, Indianapolis, Ind. USA), Effectene™, PolyFect®, Superfect® (Qiagen, Inc., Valencia, Calif., USA). Protocols for electroporating mammalian cells can be found online in Electroprotocols (Bio-Rad, Richmond, Calif., USA) (http://www.bio-rad.com/LifeScience/pdf/New_Gene_Pulser.pdf); Norton et al. (eds.), Gene Transfer Methods: Introducing DNA into Living Cells and Organisms, BioTechniques Books, Eaton Publishing Co. (2000); incorporated herein by reference in its entirety. Other transfection techniques include transfection by particle bombardment and microinjection. See, e.g., Cheng et al., Proc. Natl. Acad. Sci. USA 90(10): 4455-9 (1993); Yang et al., Proc. Natl. Acad. Sci. USA 87(24): 9568-72 (1990).

[0209] Production of the recombinantly produced proteins of the present invention can optionally be followed by purification.

[0210] Purification of recombinantly expressed proteins is now well by those skilled in the art. See, e.g., Thorner et al. (eds.), Applications of Chimeric Genes and Hybrid Proteins, Part A: Gene Expression and Protein Purification (Methods in Enzymology, Vol. 326), Academic Press (2000); Harbin (ed.), Cloning, Gene Expression and Protein Purification: Experimental Procedures and Process Rationale, Oxford Univ. Press (2001); Marshak et al., Strategies for Protein Purification and Characterization: A Laboratory Course Manual, Cold Spring Harbor Laboratory Press (1996); and Roe (ed.), Protein Purification Applications, Oxford University Press (2001); the disclosures of which are incorporated herein by reference in their entireties, and thus need not be detailed here.

[0211] Briefly, however, if purification tags have been fused through use of an expression vector that appends such tags, purification can be effected, at least in part, by means appropriate to the tag, such as use of immobilized metal affinity chromatography for polyhistidine tags. Other techniques common in the art include ammonium sulfate fractionation, immunoprecipitation, fast protein liquid chromatography (FPLC), high performance liquid chromatography (HPLC), and preparative gel electrophoresis.

[0212] Polypeptides

[0213] Another object of the invention is to provide polypeptides encoded by the nucleic acid molecules of the instant invention. In a preferred embodiment, the polypeptide is a breast specific polypeptide (BSP). In an even more preferred embodiment, the polypeptide is derived from a polypeptide comprising the amino acid sequence of SEQ ID NO: 172 through 295. A polypeptide as defined herein may be produced recombinantly, as discussed supra, may be isolated from a cell that naturally expresses the protein, or may be chemically synthesized following the teachings of the specification and using methods well-known to those having ordinary skill in the art.

[0214] In another aspect, the polypeptide may comprise a fragment of a polypeptide, wherein the fragment is as defined herein. In a preferred embodiment, the polypeptide fragment is a fragment of a BSP. In a more preferred embodiment, the fragment is derived from a polypeptide comprising the amino acid sequence of SEQ ID NO: 172 through 295. A polypeptide that comprises only a fragment of an entire BSP may or may not be a polypeptide that is also a BSP. For instance, a full-length polypeptide may be breast-specific, while a fragment thereof may be found in other tissues as well as in breast. A polypeptide that is not a BSP, whether it is a fragment, analog, mutein, homologous protein or derivative, is nevertheless useful, especially for immunizing animals to prepare anti-BSP antibodies. However, in a preferred embodiment, the part or fragment is a BSP. Methods of determining whether a polypeptide is a BSP are described infra.

[0215] Fragments of at least 6 contiguous amino acids are useful in mapping B cell and T cell epitopes of the reference protein. See, e.g., Geysen et al., Proc. Natl. Acad. Sci. USA 81: 3998-4002 (1984) and U.S. Pat. Nos. 4,708,871 and 5,595,915, the disclosures of which are incorporated herein by reference in their entireties. Because the fragment need not itself be immunogenic, part of an immunodominant epitope, nor even recognized by native antibody, to be useful in such epitope mapping, all fragments of at least 6 amino acids of the proteins of the present invention have utility in such a study.

[0216] Fragments of at least 8 contiguous amino acids, often at least 15 contiguous amino acids, are useful as immunogens for raising antibodies that recognize the proteins of the present invention. See, e.g., Lerner, Nature 299: 592-596 (1982); Shinnick et al., Annu. Rev. Microbiol. 37: 425-46 (1983); Sutcliffe et al., Science 219: 660-6 (1983), the disclosures of which are incorporated herein by reference in their entireties. As further described in the above-cited references, virtually all 8-mers, conjugated to a carrier, such as a protein, prove immunogenic, meaning that they are capable of eliciting antibody for the conjugated peptide; accordingly, all fragments of at least 8 amino acids of the proteins of the present invention have utility as immunogens.

[0217] Fragments of at least 8, 9, 10 or 12 contiguous amino acids are also useful as competitive inhibitors of binding of the entire protein, or a portion thereof, to antibodies (as in epitope mapping), and to natural binding partners, such as subunits in a multimeric complex or to receptors or ligands of the subject protein; this competitive inhibition permits identification and separation of molecules that bind specifically to the protein of interest, U.S. Pat. Nos. 5,539,084 and 5,783,674, incorporated herein by reference in their entireties.

[0218] The protein, or protein fragment, of the present invention is thus at least 6 amino acids in length, typically at least 8, 9, 10 or 12 amino acids in length, and often at least 15 amino acids in length. Often, the protein of the present invention, or fragment thereof, is at least 20 amino acids in length, even 25 amino acids, 30 amino acids, 35 amino acids, or 50 amino acids or more in length. Of course, larger fragments having at least 75 amino acids, 100 amino acids, or even 150 amino acids are also useful, and at times preferred.

[0219] One having ordinary skill in the art can produce fragments of a polypeptide by truncating the nucleic acid molecule, e.g., a BSNA, encoding the polypeptide and then expressing it recombinantly. Alternatively, one can produce a fragment by chemically synthesizing a portion of the full-length polypeptide. One may also produce a fragment by enzymatically cleaving either a recombinant polypeptide or an isolated naturally-occurring polypeptide. Methods of producing polypeptide fragments are well-known in the art. See, e.g., Sambrook (1989), supra; Sambrook (2001), supra; Ausubel (1992), supra; and Ausubel (1999), supra. In one embodiment, a polypeptide comprising only a fragment of polypeptide of the invention, preferably a BSP, may be produced by chemical or enzymatic cleavage of a polypeptide. In a preferred embodiment, a polypeptide fragment is produced by expressing a nucleic acid molecule encoding a fragment of the polypeptide, preferably a BSP, in a host cell.

[0220] By “polypeptides” as used herein it is also meant to be inclusive of mutants, fusion proteins, homologous proteins and allelic variants of the polypeptides specifically exemplified.

[0221] A mutant protein, or mutein, may have the same or different properties compared to a naturally-occurring polypeptide and comprises at least one amino acid insertion, duplication, deletion, rearrangement or substitution compared to the amino acid sequence of a native protein. Small deletions and insertions can often be found that do not alter the function of the protein. In one embodiment, the mutein may or may not be breast-specific. In a preferred embodiment, the mutein is breast-specific. In a preferred embodiment, the mutein is a polypeptide that comprises at least one amino acid insertion, duplication, deletion, rearrangement or substitution compared to the amino acid sequence of SEQ ID NO: 172 through 295. In a more preferred embodiment, the mutein is one that exhibits at least 50% sequence identity, more preferably at least 60% sequence identity, even more preferably at least 70%, yet more preferably at least 80% sequence identity to a BSP comprising an amino acid sequence of SEQ ID NO: 172 through 295. In yet a more preferred embodiment, the mutein exhibits at least 85%, more preferably 90%, even more preferably 95% or 96%, and yet more preferably at least 97%, 98%, 99% or 99.5% sequence identity to a BSP comprising an amino acid sequence of SEQ ID NO: 172 through 295.

[0222] A mutein may be produced by isolation from a naturally-occurring mutant cell, tissue or organism. A mutein may be produced by isolation from a cell, tissue or organism that has been experimentally mutagenized. Alternatively, a mutein may be produced by chemical manipulation of a polypeptide, such as by altering the amino acid residue to another amino acid residue using synthetic or semi-synthetic chemical techniques. In a preferred embodiment, a mutein may be produced from a host cell comprising an altered nucleic acid molecule compared to the naturally-occurring nucleic acid molecule. For instance, one may produce a mutein of a polypeptide by introducing one or more mutations into a nucleic acid sequence of the invention and then expressing it recombinantly. These mutations may be targeted, in which particular encoded amino acids are altered, or may be untargeted, in which random encoded amino acids within the polypeptide are altered. Muteins with random amino acid alterations can be screened for a particular biological activity or property, particularly whether the polypeptide is breast-specific, as described below. Multiple random mutations can be introduced into the gene by methods well-known to the art, e.g., by error-prone PCR, shuffling, oligonucleotide-directed mutagenesis, assembly PCR, sexual PCR mutagenesis, in vivo mutagenesis, cassette mutagenesis, recursive ensemble mutagenesis, exponential ensemble mutagenesis and site-specific mutagenesis. Methods of producing muteins with targeted or random amino acid alterations are well-known in the art. See, e.g., Sambrook (1989), supra; Sambrook (2001), supra; Ausubel (1992), supra; and Ausubel (1999), U.S. Pat. No. 5,223,408, and the references discussed supra, each herein incorporated by reference.

[0223] By “polypeptide” as used herein it is also meant to be inclusive of polypeptides homologous to those polypeptides exemplified herein. In a preferred embodiment, the polypeptide is homologous to a BSP. In an even more preferred embodiment, the polypeptide is homologous to a BSP selected from the group having an amino acid sequence of SEQ ID NO: 172 through 295. In a preferred embodiment, the homologous polypeptide is one that exhibits significant sequence identity to a BSP. In a more preferred embodiment, the polypeptide is one that exhibits significant sequence identity to an comprising an amino acid sequence of SEQ ID NO: 172 through 295. In an even more preferred embodiment, the homologous polypeptide is one that exhibits at least 50% sequence identity, more preferably at least 60% sequence identity, even more preferably at least 70%, yet more preferably at least 80% sequence identity to a BSP comprising an amino acid sequence of SEQ ID NO: 172 through 295. In a yet more preferred embodiment, the homologous polypeptide is one that exhibits at least 85%, more preferably 90%, even more preferably 95% or 96%, and yet more preferably at least 97% or 98% sequence identity to a BSP comprising an amino acid sequence of SEQ ID NO: 172 through 295. In another preferred embodiment, the homologous polypeptide is one that exhibits at least 99%, more preferably 99.5%, even more preferably 99.6%, 99.7%, 99.8% or 99.9% sequence identity to a BSP comprising an amino acid sequence of SEQ ID NO: 172 through 295. In a preferred embodiment, the amino acid substitutions are conservative amino acid substitutions as discussed above.

[0224] In another embodiment, the homologous polypeptide is one that is encoded by a nucleic acid molecule that selectively hybridizes to a BSNA. In a preferred embodiment, the homologous polypeptide is encoded by a nucleic acid molecule that hybridizes to a BSNA under low stringency, moderate stringency or high stringency conditions, as defined herein. In a more preferred embodiment, the BSNA is selected from the group consisting of SEQ ID NO: 1 through 171. In another preferred embodiment, the homologous polypeptide is encoded by a nucleic acid molecule that hybridizes to a nucleic acid molecule that encodes a BSP under low stringency, moderate stringency or high stringency conditions, as defined herein. In a more preferred embodiment, the BSP is selected from the group consisting of SEQ ID NO: 172 through 295.

[0225] The homologous polypeptide may be a naturally-occurring one that is derived from another species, especially one derived from another primate, such as chimpanzee, gorilla, rhesus macaque, baboon or gorilla, wherein the homologous polypeptide comprises an amino acid sequence that exhibits significant sequence identity to that of SEQ ID NO: 172 through 295. The homologous polypeptide may also be a naturally-occurring polypeptide from a human, when the BSP is a member of a family of polypeptides. The homologous polypeptide may also be a naturally-occurring polypeptide derived from a non-primate, mammalian species, including without limitation, domesticated species, e.g., dog, cat, mouse, rat, rabbit, guinea pig, hamster, cow, horse, goat or pig. The homologous polypeptide may also be a naturally-occurring polypeptide derived from a non-mammalian species, such as birds or reptiles. The naturally-occurring homologous protein may be isolated directly from humans or other species. Alternatively, the nucleic acid molecule encoding the naturally-occurring homologous polypeptide may be isolated and used to express the homologous polypeptide recombinantly. In another embodiment, the homologous polypeptide may be one that is experimentally produced by random mutation of a nucleic acid molecule and subsequent expression of the nucleic acid molecule. In another embodiment, the homologous polypeptide may be one that is experimentally produced by directed mutation of one or more codons to alter the encoded amino acid of a BSP. Further, the homologous protein may or may not encode polypeptide that is a BSP. However, in a preferred embodiment, the homologous polypeptide encodes a polypeptide that is a BSP.

[0226] Relatedness of proteins can also be characterized using a second functional test, the ability of a first protein competitively to inhibit the binding of a second protein to an antibody. It is, therefore, another aspect of the present invention to provide isolated proteins not only identical in sequence to those described with particularity herein, but also to provide isolated proteins (“cross-reactive proteins”) that competitively inhibit the binding of antibodies to all or to a portion of various of the isolated polypeptides of the present invention. Such competitive inhibition can readily be determined using immunoassays well-known in the art.

[0227] As discussed above, single nucleotide polymorphisms (SNPs) occur frequently in eukaryotic genomes, and the sequence determined from one individual of a species may differ from other allelic forms present within the population. Thus, by “polypeptide” as used herein it is also meant to be inclusive of polypeptides encoded by an allelic variant of a nucleic acid molecule encoding a BSP. In a preferred embodiment, the polypeptide is encoded by an allelic variant of a gene that encodes a polypeptide having the amino acid sequence selected from the group consisting of SEQ ID NO: 172 through 295. In a yet more preferred embodiment, the polypeptide is encoded by an allelic variant of a gene that has the nucleic acid sequence selected from the group consisting of SEQ ID NO: 1 through 171.

[0228] In another embodiment, the invention provides polypeptides which comprise derivatives of a polypeptide encoded by a nucleic acid molecule according to the instant invention. In a preferred embodiment, the polypeptide is a BSP. In a preferred embodiment, the polypeptide has an amino acid sequence selected from the group consisting of SEQ ID NO: 172 through 295, or is a mutein, allelic variant, homologous protein or fragment thereof. In a preferred embodiment, the derivative has been acetylated, carboxylated, phosphorylated, glycosylated or ubiquitinated. In another preferred embodiment, the derivative has been labeled with, e.g., radioactive isotopes such as ¹²⁵I, ³²P, ³⁵S, and ³H. In another preferred embodiment, the derivative has been labeled with fluorophores, chemiluminescent agents, enzymes, and antiligands that can serve as specific binding pair members for a labeled ligand.

[0229] Polypeptide modifications are well-known to those of skill and have been described in great detail in the scientific literature. Several particularly common modifications, glycosylation, lipid attachment, sulfation, gamma-carboxylation of glutamic acid residues, hydroxylation and ADP-ribosylation, for instance, are described in most basic texts, such as, for instance Creighton, Protein Structure and Molecular Properties, 2nd ed., W.H. Freeman and Company (1993). Many detailed reviews are available on this subject, such as, for example, those provided by Wold, in Johnson (ed.), Posttranslational Covalent Modification of Proteins, pgs. 1-12, Academic Press (1983); Seifter et al., Meth. Enzymol. 182: 626-646 (1990) and Rattan et al., Ann. N.Y. Acad. Sci. 663: 48-62 (1992).

[0230] It will be appreciated, as is well-known and as noted above, that polypeptides are not always entirely linear. For instance, polypeptides may be branched as a result of ubiquitination, and they may be circular, with or without branching, generally as a result of posttranslation events, including natural processing event and events brought about by human manipulation which do not occur naturally. Circular, branched and branched circular polypeptides may be synthesized by non-translation natural process and by entirely synthetic methods, as well. Modifications can occur anywhere in a polypeptide, including the peptide backbone, the amino acid side-chains and the amino or carboxyl termini. In fact, blockage of the amino or carboxyl group in a polypeptide, or both, by a covalent modification, is common in naturally occurring and synthetic polypeptides and such modifications may be present in polypeptides of the present invention, as well. For instance, the amino terminal residue of polypeptides made in E. coli, prior to proteolytic processing, almost invariably will be N-formylmethionine.

[0231] Useful post-synthetic (and post-translational) modifications include conjugation to detectable labels, such as fluorophores. A wide variety of amine-reactive and thiol-reactive fluorophore derivatives have been synthesized that react under nondenaturing conditions with N-terminal amino groups and epsilon amino groups of lysine residues, on the one hand, and with free thiol groups of cysteine residues, on the other.

[0232] Kits are available commercially that permit conjugation of proteins to a variety of amine-reactive or thiol-reactive fluorophores: Molecular Probes, Inc. (Eugene, Oreg., USA), e.g., offers kits for conjugating proteins to Alexa Fluor 350, Alexa Fluor 430, Fluorescein-EX, Alexa Fluor 488, Oregon Green 488, Alexa Fluor 532, Alexa Fluor 546, Alexa Fluor 546, Alexa Fluor 568, Alexa Fluor 594, and Texas Red-X.

[0233] A wide variety of other amine-reactive and thiol-reactive fluorophores are available commercially (Molecular Probes, Inc., Eugene, Oreg., USA), including Alexa Fluor® 350, Alexa Fluor® 488, Alexa Fluor® 532, Alexa Fluor® 546, Alexa Fluor® 568, Alexa Fluor® 594, Alexa Fluor® 647 (monoclonal antibody labeling kits available from Molecular Probes, Inc., Eugene, Oreg., USA), BODIPY dyes, such as BODIPY 493/503, BODIPY FL, BODIPY R6G, BODIPY 530/550, BODIPY TMR, BODIPY 558/568, BODIPY 558/568, BODIPY 564/570, BODIPY 576/589, BODIPY 581/591, BODIPY TR, BODIPY 630/650, BODIPY 650/665, Cascade Blue, Cascade Yellow, Dansyl, lissamine rhodamine B, Marina Blue, Oregon Green 488, Oregon Green 514, Pacific Blue, rhodamine 6G, rhodamine green, rhodamine red, tetramethylrhodamine, Texas Red (available from Molecular Probes, Inc., Eugene, Oreg., USA).

[0234] The polypeptides of the present invention can also be conjugated to fluorophores, other proteins, and other macromolecules, using bifunctional linking reagents. Common homobifunctional reagents include, e.g., APG, AEDP, BASED, BMB, BMDB, BMH, BMOE, BM[PEO]3, BM[PEO]4, BS3, BSOCOES, DFDNB, DMA, DMP, DMS, DPDPB, DSG, DSP (Lomant's Reagent), DSS, DST, DTBP, DTME, DTSSP, EGS, HBVS, Sulfo-BSOCOES, Sulfo-DST, Sulfo-EGS (all available from Pierce, Rockford, Ill., USA); common heterobifunctional cross-linkers include ABH, AMAS, ANB-NOS, APDP, ASBA, BMPA, BMPH, BMPS, EDC, EMCA, EMCH, EMCS, KMUA, KMUH, GMBS, LC-SMCC, LC-SPDP, MBS, M2C2H, MPBH, MSA, NHS-ASA, PDPH, PMPI, SADP, SAED, SAND, SANPAH, SASD, SATP, SBAP, SFAD, SIA, SIAB, SMCC, SMPB, SMPH, SMPT, SPDP, Sulfo-EMCS, Sulfo-GMBS, Sulfo-HSAB, Sulfo-KMUS, Sulfo-LC-SPDP, Sulfo-MBS, Sulfo-NHS-LC-ASA, Sulfo-SADP, Sulfo-SANPAH, Sulfo-SIAB, Sulfo-SMCC, Sulfo-SMPB, Sulfo-LC-SMPT, SVSB, TFCS (all available Pierce, Rockford, Ill., USA).

[0235] The polypeptides, fragments, and fusion proteins of the present invention can be conjugated, using such cross-linking reagents, to fluorophores that are not amine- or thiol-reactive. Other labels that usefully can be conjugated to the polypeptides, fragments, and fusion proteins of the present invention include radioactive labels, echosonographic contrast reagents, and MRI contrast agents.

[0236] The polypeptides, fragments, and fusion proteins of the present invention can also usefully be conjugated using cross-linking agents to carrier proteins, such as KLH, bovine thyroglobulin, and even bovine serum albumin (BSA), to increase immunogenicity for raising anti-BSP antibodies.

[0237] The polypeptides, fragments, and fusion proteins of the present invention can also usefully be conjugated to polyethylene glycol (PEG); PEGylation increases the serum half-life of proteins administered intravenously for replacement therapy. Delgado et al., Crit. Rev. Ther. Drug Carrier Syst. 9(3-4): 249-304 (1992); Scott et al., Curr. Pharm. Des. 4(6): 423-38 (1998); DeSantis et al., Curr. Opin. Biotechnol. 10(4): 324-30 (1999), incorporated herein by reference in their entireties. PEG monomers can be attached to the protein directly or through a linker, with PEGylation using PEG monomers activated with tresyl chloride (2,2,2-trifluoroethanesulphonyl chloride) permitting direct attachment under mild conditions.

[0238] In yet another embodiment, the invention provides analogs of a polypeptide encoded by a nucleic acid molecule according to the instant invention. In a preferred embodiment, the polypeptide is a BSP. In a more preferred embodiment, the analog is derived from a polypeptide having part or all of the amino acid sequence of SEQ ID NO: 172 through 295. In a preferred embodiment, the analog is one that comprises one or more substitutions of non-natural amino acids or non-native inter-residue bonds compared to the naturally-occurring polypeptide. In general, the non-peptide analog is structurally similar to a BSP, but one or more peptide linkages is replaced by a linkage selected from the group consisting of —CH₂NH—, —CH₂S—, —CH₂—CH₂—, —CH═CH-(cis and trans), —COCH₂—, —CH(OH)CH₂— and —CH₂SO—. In another embodiment, the non-peptide analog comprises substitution of one or more amino acids of a BSP with a D-amino acid of the same type or other non-natural amino acid in order to generate more stable peptides. D-amino acids can readily be incorporated during chemical peptide synthesis: peptides assembled from D-amino acids are more resistant to proteolytic attack; incorporation of D-amino acids can also be used to confer specific three-dimensional conformations on the peptide. Other amino acid analogues commonly added during chemical synthesis include ornithine, norleucine, phosphorylated amino acids (typically phosphoserine, phosphothreonine, phosphotyrosine), L-malonyltyrosine, a non-hydrolyzable analog of phosphotyrosine (see, e.g., Kole et al., Biochem. Biophys. Res. Com. 209: 817-821 (1995)), and various halogenated phenylalanine derivatives.

[0239] Non-natural amino acids can be incorporated during solid phase chemical synthesis or by recombinant techniques, although the former is typically more common. Solid phase chemical synthesis of peptides is well established in the art. Procedures are described, inter alia, in Chan et al. (eds.), Fmoc Solid Phase Peptide Synthesis: A Practical Approach (Practical Approach Series), Oxford Univ. Press (March 2000); Jones, Amino Acid and Peptide Synthesis (Oxford Chemistry Primers, No 7), Oxford Univ. Press (1992); and Bodanszky, Principles of Peptide Synthesis (Springer Laboratory), Springer Verlag (1993); the disclosures of which are incorporated herein by reference in their entireties.

[0240] Amino acid analogues having detectable labels are also usefully incorporated during synthesis to provide derivatives and analogs. Biotin, for example can be added using biotinoyl-(9-fluorenylmethoxycarbonyl)-L-lysine (FMOC biocytin) (Molecular Probes, Eugene, Oreg., USA). Biotin can also be added enzymatically by incorporation into a fusion protein of a E. coli BirA substrate peptide. The FMOC and tBOC derivatives of dabcyl-L-lysine (Molecular Probes, Inc., Eugene, Oreg., USA) can be used to incorporate the dabcyl chromophore at selected sites in the peptide sequence during synthesis. The aminonaphthalene derivative EDANS, the most common fluorophore for pairing with the dabcyl quencher in fluorescence resonance energy transfer (FRET) systems, can be introduced during automated synthesis of peptides by using EDANS-FMOC-L-glutamic acid or the corresponding tBOC derivative (both from Molecular Probes, Inc., Eugene, Oreg., USA). Tetramethylrhodamine fluorophores can be incorporated during automated FMOC synthesis of peptides using (FMOC)-TMR-L-lysine (Molecular Probes, Inc. Eugene, Oreg., USA).

[0241] Other useful amino acid analogues that can be incorporated during chemical synthesis include aspartic acid, glutamic acid, lysine, and tyrosine analogues having allyl side-chain protection (Applied Biosystems, Inc., Foster City, Calif., USA); the allyl side chain permits synthesis of cyclic, branched-chain, sulfonated, glycosylated, and phosphorylated peptides.

[0242] A large number of other FMOC-protected non-natural amino acid analogues capable of incorporation during chemical synthesis are available commercially, including, e.g., Fmoc-2-aminobicyclo[2.2.1]heptane-2-carboxylic acid, Fmoc-3-endo-aminobicyclo[2.2.1]heptane-2-endo-carboxylic acid, Fmoc-3-exo-aminobicyclo[2.2.1]heptane-2-exo-carboxylic acid, Fmoc-3-endo-aminobicyclo[2.2.1]hept-5-ene-2-endo-carboxylic acid, Fmoc-3-exo-amino-bicyclo[2.2.1]hept-5-ene-2-exo-carboxylic acid, Fmoc-cis-2-amino-1-cyclohexanecarboxylic acid, Fmoc-trans-2-amino-1-cyclohexanecarboxylic acid, Fmoc-1-amino-1-cyclopentanecarboxylic acid, Fmoc-cis-2-amino-1-cyclopentanecarboxylic acid, Fmoc-1-amino-1-cyclopropanecarboxylic acid, Fmoc-D-2-amino-4-(ethylthio)butyric acid, Fmoc-L-2-amino-4-(ethylthio)butyric acid, Fmoc-L-buthionine, Fmoc-S-methyl-L-Cysteine, Fmoc-2-aminobenzoic acid (anthranillic acid), Fmoc-3-aminobenzoic acid, Fmoc-4-aminobenzoic acid, Fmoc-2-aminobenzophenone-2′-carboxylic acid, Fmoc-N-(4-aminobenzoyl)-β-alanine, Fmoc-2-amino-4,5-dimethoxybenzoic acid, Fmoc-4-aminohippuric acid, Fmoc-2-amino-3-hydroxybenzoic acid, Fmoc-2-amino-5-hydroxybenzoic acid, Fmoc-3-amino-4-hydroxybenzoic acid, Fmoc-4-amino-3-hydroxybenzoic acid, Fmoc-4-amino-2-hydroxybenzoic acid, Fmoc-5-amino-2-hydroxybenzoic acid, Fmoc-2-amino-3-methoxybenzoic acid, Fmoc-4-amino-3-methoxybenzoic acid, Fmoc-2-amino-3-methylbenzoic acid, Fmoc-2-amino-5-methylbenzoic acid, Fmoc-2-amino-6-methylbenzoic acid, Fmoc-3-amino-2-methylbenzoic acid, Fmoc-3-amino-4-methylbenzoic acid, Fmoc-4-amino-3-methylbenzoic acid, Fmoc-3-amino-2-naphtoic acid, Fmoc-D,L-3-amino-3-phenylpropionic acid, Fmoc-L-Methyldopa, Fmoc-2-amino-4,6-dimethyl-3-pyridinecarboxylic acid, Fmoc-D,L-amino-2-thiophenacetic acid, Fmoc-4-(carboxymethyl)piperazine, Fmoc-4-carboxypiperazine, Fmoc-4-(carboxymethyl)homopiperazine, Fmoc-4-phenyl-4-piperidinecarboxylic acid, Fmoc-L-1,2,3,4-tetrahydronorharman-3-carboxylic acid, Fmoc-L-thiazolidine-4-carboxylic acid, all available from The Peptide Laboratory (Richmond, Calif., USA).

[0243] Non-natural residues can also be added biosynthetically by engineering a suppressor tRNA, typically one that recognizes the UAG stop codon, by chemical aminoacylation with the desired unnatural amino acid. Conventional site-directed mutagenesis is used to introduce the chosen stop codon UAG at the site of interest in the protein gene. When the acylated suppressor tRNA and the mutant gene are combined in an in vitro transcription/translation system, the unnatural amino acid is incorporated in response to the UAG codon to give a protein containing that amino acid at the specified position. Liu et al., Proc. Natl. Acad. Sci. USA 96(9): 4780-5 (1999); Wang et al., Science 292(5516): 498-500 (2001).

[0244] Fusion Proteins

[0245] The present invention further provides fusions of each of the polypeptides and fragments of the present invention to heterologous polypeptides. In a preferred embodiment, the polypeptide is a BSP. In a more preferred embodiment, the polypeptide that is fused to the heterologous polypeptide comprises part or all of the amino acid sequence of SEQ ID NO: 172 through 295, or is a mutein, homologous polypeptide, analog or derivative thereof. In an even more preferred embodiment, the nucleic acid molecule encoding the fusion protein comprises all or part of the nucleic acid sequence of SEQ ID NO: 1 through 171, or comprises all or part of a nucleic acid sequence that selectively hybridizes or is homologous to a nucleic acid molecule comprising a nucleic acid sequence of SEQ ID NO: 1 through 171.

[0246] The fusion proteins of the present invention will include at least one fragment of the protein of the present invention, which fragment is at least 6, typically at least 8, often at least 15, and usefully at least 16, 17, 18, 19, or 20 amino acids long. The fragment of the protein of the present to be included in the fusion can usefully be at least 25 amino acids long, at least 50 amino acids long, and can be at least 75, 100, or even 150 amino acids long. Fusions that include the entirety of the proteins of the present invention have particular utility.

[0247] The heterologous polypeptide included within the fusion protein of the present invention is at least 6 amino acids in length, often at least 8 amino acids in length, and usefully at least 15, 20, and 25 amino acids in length. Fusions that include larger polypeptides, such as the IgG Fc region, and even entire proteins (such as GFP chromophore-containing proteins) are particular useful.

[0248] As described above in the description of vectors and expression vectors of the present invention, which discussion is incorporated here by reference in its entirety, heterologous polypeptides to be included in the fusion proteins of the present invention can usefully include those designed to facilitate purification and/or visualization of recombinantly-expressed proteins. See, e.g., Ausubel, Chapter 16, (1992), supra. Although purification tags can also be incorporated into fusions that are chemically synthesized, chemical synthesis typically provides sufficient purity that further purification by HPLC suffices; however, visualization tags as above described retain their utility even when the protein is produced by chemical synthesis, and when so included render the fusion proteins of the present invention useful as directly detectable markers of the presence of a polypeptide of the invention.

[0249] As also discussed above, heterologous polypeptides to be included in the fusion proteins of the present invention can usefully include those that facilitate secretion of recombinantly expressed proteins—into the periplasmic space or extracellular milieu for prokaryotic hosts, into the culture medium for eukaryotic cells—through incorporation of secretion signals and/or leader sequences. For example, a His⁶ tagged protein can be purified on a Ni affinity column and a GST fusion protein can be purified on a glutathione affinity column. Similarly, a fusion protein comprising the Fc domain of IgG can be purified on a Protein A or Protein G column and a fusion protein comprising an epitope tag such as myc can be purified using an immunoaffinity column containing an anti-c-myc antibody. It is preferable that the epitope tag be separated from the protein encoded by the essential gene by an enzymatic cleavage site that can be cleaved after purification. See also the discussion of nucleic acid molecules encoding fusion proteins that may be expressed on the surface of a cell.

[0250] Other useful protein fusions of the present invention include those that permit use of the protein of the present invention as bait in a yeast two-hybrid system. See Bartel et al. (eds.), The Yeast Two-Hybrid System, Oxford University Press (1997); Zhu et al., Yeast Hybrid Technologies, Eaton Publishing (2000); Fields et al., Trends Genet. 10(8): 286-92 (1994); Mendelsohn et al., Curr. Opin. Biotechnol. 5(5): 482-6 (1994); Luban et al., Curr. Opin. Biotechnol. 6(1): 59-64 (1995); Allen et al., Trends Biochem. Sci. 20(12): 511-6 (1995); Drees, Curr. Opin. Chem. Biol. 3(1): 64-70 (1999); Topcu et al., Pharm. Res. 17(9): 1049-55 (2000); Fashena et al., Gene 250(1-2): 1-14 (2000); Colas et al., (1996) Genetic selection of peptide aptamers that recognize and inhibit cyclin-dependent kinase 2. Nature 380, 548-550; Norman, T. et al., (1999) Genetic selection of peptide inhibitors of biological pathways. Science 285, 591-595, Fabbrizio et al., (1999) Inhibition of mammalian cell proliferation by genetically selected peptide aptamers that functionally antagonize E2F activity. Oncogene 18, 4357-4363; Xu et al., (1997) Cells that register logical relationships among proteins. Proc Natl Acad Sci USA. 94, 12473-12478; Yang, et al., (1995) Protein-peptide interactions analyzed with the yeast two-hybrid system. Nuc. Acids Res. 23, 1152-1156; Kolonin et al., (1998) Targeting cyclin-dependent kinases in Drosophila with peptide aptamers. Proc Natl Acad Sci USA 95, 14266-14271; Cohen et al., (1998) An artificial cell-cycle inhibitor isolated from a combinatorial library. Proc Natl Acad Sci USA 95, 14272-14277; Uetz, P.; Giot, L.; al, e.; Fields, S.; Rothberg, J. M. (2000) A comprehensive analysis of protein-protein interactions in Saccharomyces cerevisiae. Nature 403, 623-627; Ito, et al., (2001) A comprehensive two-hybrid analysis to explore the yeast protein interactome. Proc Natl Acad Sci USA 98, 4569-4574, the disclosures of which are incorporated herein by reference in their entireties. Typically, such fusion is to either E. coli LexA or yeast GAL4 DNA binding domains. Related bait plasmids are available that express the bait fused to a nuclear localization signal.

[0251] Other useful fusion proteins include those that permit display of the encoded protein on the surface of a phage or cell, fusions to intrinsically fluorescent proteins, such as green fluorescent protein (GFP), and fusions to the IgG Fc region, as described above, which discussion is incorporated here by reference in its entirety.

[0252] The polypeptides and fragments of the present invention can also usefully be fused to protein toxins, such as Pseudomonas exotoxin A, diphtheria toxin, shiga toxin A, anthrax toxin lethal factor, ricin, in order to effect ablation of cells that bind or take up the proteins of the present invention.

[0253] Fusion partners include, inter alia, myc, hemagglutinin (HA), GST, immunoglobulins, β-galactosidase, biotin trpE, protein A, β-lactamase, α-amylase, maltose binding protein, alcohol dehydrogenase, polyhistidine (for example, six histidine at the amino and/or carboxyl terminus of the polypeptide), lacZ, green fluorescent protein (GFP), yeast α mating factor, GAL4 transcription activation or DNA binding domain, luciferase, and serum proteins such as ovalbumin, albumin and the constant domain of IgG. See, e.g., Ausubel (1992), supra and Ausubel (1999), supra. Fusion proteins may also contain sites for specific enzymatic cleavage, such as a site that is recognized by enzymes such as Factor XIII, trypsin, pepsin, or any other enzyme known in the art. Fusion proteins will typically be made by either recombinant nucleic acid methods, as described above, chemically synthesized using techniques well-known in the art (e.g., a Merrifield synthesis), or produced by chemical cross-linking.

[0254] Another advantage of fusion proteins is that the epitope tag can be used to bind the fusion protein to a plate or column through an affinity linkage for screening binding proteins or other molecules that bind to the BSP.

[0255] As further described below, the isolated polypeptides, muteins, fusion proteins, homologous proteins or allelic variants of the present invention can readily be used as specific immunogens to raise antibodies that specifically recognize BSPs, their allelic variants and homologues. The antibodies, in turn, can be used, inter alia, specifically to assay for the polypeptides of the present invention, particularly BSPs, e.g. by ELISA for detection of protein fluid samples, such as serum, by immunohistochemistry or laser scanning cytometry, for detection of protein in tissue samples, or by flow cytometry, for detection of intracellular protein in cell suspensions, for specific antibody-mediated isolation and/or purification of BSPs, as for example by immunoprecipitation, and for use as specific agonists or antagonists of BSPs.

[0256] One may determine whether polypeptides including muteins, fusion proteins, homologous proteins or allelic variants are functional by methods known in the art. For instance, residues that are tolerant of change while retaining function can be identified by altering the protein at known residues using methods known in the art, such as alanine scanning mutagenesis, Cunningham et al., Science 244(4908): 1081-5 (1989); transposon linker scanning mutagenesis, Chen et al., Gene 263(1-2): 39-48 (2001); combinations of homolog- and alanine-scanning mutagenesis, Jin et al., J. Mol. Biol. 226(3): 851-65 (1992); combinatorial alanine scanning, Weiss et al., Proc. Natl. Acad. Sci USA 97(16): 8950-4 (2000), followed by functional assay. Transposon linker scanning kits are available commercially (New England Biolabs, Beverly, Mass., USA, catalog. no. E7-102S; EZ::TN™ In-Frame Linker Insertion Kit, catalogue no. EZI04KN, Epicentre Technologies Corporation, Madison, Wis., USA).

[0257] Purification of the polypeptides including fragments, homologous polypeptides, muteins, analogs, derivatives and fusion proteins is well-known and within the skill of one having ordinary skill in the art. See, e.g., Scopes, Protein Purification, 2d ed. (1987). Purification of recombinantly expressed polypeptides is described above. Purification of chemically-synthesized peptides can readily be effected, e.g., by HPLC.

[0258] Accordingly, it is an aspect of the present invention to provide the isolated proteins of the present invention in pure or substantially pure form in the presence of absence of a stabilizing agent. Stabilizing agents include both proteinaceous or non-proteinaceous material and are well-known in the art. Stabilizing agents, such as albumin and polyethylene glycol (PEG) are known and are commercially available.

[0259] Although high levels of purity are preferred when the isolated proteins of the present invention are used as therapeutic agents, such as in vaccines and as replacement therapy, the isolated proteins of the present invention are also useful at lower purity. For example, partially purified proteins of the present invention can be used as immunogens to raise antibodies in laboratory animals.

[0260] In preferred embodiments, the purified and substantially purified proteins of the present invention are in compositions that lack detectable ampholytes, acrylamide monomers, bis-acrylamide monomers, and polyacrylamide.

[0261] The polypeptides, fragments, analogs, derivatives and fusions of the present invention can usefully be attached to a substrate. The substrate can be porous or solid, planar or non-planar; the bond can be covalent or noncovalent.

[0262] For example, the polypeptides, fragments, analogs, derivatives and fusions of the present invention can usefully be bound to a porous substrate, commonly a membrane, typically comprising nitrocellulose, polyvinylidene fluoride (PVDF), or cationically derivatized, hydrophilic PVDF; so bound, the proteins, fragments, and fusions of the present invention can be used to detect and quantify antibodies, e.g. in serum, that bind specifically to the immobilized protein of the present invention.

[0263] As another example, the polypeptides, fragments, analogs, derivatives and fusions of the present invention can usefully be bound to a substantially nonporous substrate, such as plastic, to detect and quantify antibodies, e.g. in serum, that bind specifically to the immobilized protein of the present invention. Such plastics include polymethylacrylic, polyethylene, polypropylene, polyacrylate, polymethylmethacrylate, polyvinylchloride, polytetrafluoroethylene, polystyrene, polycarbonate, polyacetal, polysulfone, celluloseacetate, cellulosenitrate, nitrocellulose, or mixtures thereof; when the assay is performed in a standard microtiter dish, the plastic is typically polystyrene.

[0264] The polypeptides, fragments, analogs, derivatives and fusions of the present invention can also be attached to a substrate suitable for use as a surface enhanced laser desorption ionization source; so attached, the protein, fragment, or fusion of the present invention is useful for binding and then detecting secondary proteins that bind with sufficient affinity or avidity to the surface-bound protein to indicate biologic interaction there between. The proteins, fragments, and fusions of the present invention can also be attached to a substrate suitable for use in surface plasmon resonance detection; so attached, the protein, fragment, or fusion of the present invention is useful for binding and then detecting secondary proteins that bind with sufficient affinity or avidity to the surface-bound protein to indicate biological interaction there between.

[0265] Antibodies

[0266] In another aspect, the invention provides antibodies, including fragments and derivatives thereof, that bind specifically to polypeptides encoded by the nucleic acid molecules of the invention, as well as antibodies that bind to fragments, muteins, derivatives and analogs of the polypeptides. In a preferred embodiment, the antibodies are specific for a polypeptide that is a BSP, or a fragment, mutein, derivative, analog or fusion protein thereof. In a more preferred embodiment, the antibodies are specific for a polypeptide that comprises SEQ ID NO: 172 through 295, or a fragment, mutein, derivative, analog or fusion protein thereof.

[0267] The antibodies of the present invention can be specific for linear epitopes, discontinuous epitopes, or conformational epitopes of such proteins or protein fragments, either as present on the protein in its native conformation or, in some cases, as present on the proteins as denatured, as, e.g., by solubilization in SDS. New epitopes may be also due to a difference in post translational modifications (PTMs) in disease versus normal tissue. For example, a particular site on a BSP may be glycosylated in cancerous cells, but not glycosylated in normal cells or visa versa. In addition, alternative splice forms of a BSP may be indicative of cancer. Differential degradation of the C or N-terminus of a BSP may also be a marker or target for anticancer therapy. For example, a BSP may be N-terminal degraded in cancer cells exposing new epitopes to which antibodies may selectively bind for diagnostic or therapeutic uses.

[0268] As is well-known in the art, the degree to which an antibody can discriminate as among molecular species in a mixture will depend, in part, upon the conformational relatedness of the species in the mixture; typically, the antibodies of the present invention will discriminate over adventitious binding to non-BSP polypeptides by at least 2-fold, more typically by at least 5-fold, typically by more than 10-fold, 25-fold, 50-fold, 75-fold, and often by more than 100-fold, and on occasion by more than 500-fold or 1000-fold. When used to detect the proteins or protein fragments of the present invention, the antibody of the present invention is sufficiently specific when it can be used to determine the presence of the protein of the present invention in samples derived from human breast.

[0269] Typically, the affinity or avidity of an antibody (or antibody multimer, as in the case of an IgM pentamer) of the present invention for a protein or protein fragment of the present invention will be at least about 1×10⁻⁶ molar (M), typically at least about 5×10⁻⁷ M, 1×10⁻⁷ M, with affinities and avidities of at least 1×10⁻⁸ M, 5×10⁻⁹ M, 1×10⁻¹⁰ M and up to 1×10⁻¹³ M proving especially useful.

[0270] The antibodies of the present invention can be naturally-occurring forms, such as IgG, IgM, IgD, IgE, IgY, and IgA, from any avian, reptilian, or mammalian species.

[0271] Human antibodies can, but will infrequently, be drawn directly from human donors or human cells. In this case, antibodies to the proteins of the present invention will typically have resulted from fortuitous immunization, such as autoimmune immunization, with the protein or protein fragments of the present invention. Such antibodies will typically, but will not invariably, be polyclonal. In addition, individual polyclonal antibodies may be isolated and cloned to generate monoclonals.

[0272] Human antibodies are more frequently obtained using transgenic animals that express human immunoglobulin genes, which transgenic animals can be affirmatively immunized with the protein immunogen of the present invention. Human Ig-transgenic mice capable of producing human antibodies and methods of producing human antibodies therefrom upon specific immunization are described, inter alia, in U.S. Pat. Nos. 6,162,963; 6,150,584; 6,114,598; 6,075,181; 5,939,598; 5,877,397; 5,874,299; 5,814,318; 5,789,650; 5,770,429; 5,661,016; 5,633,425; 5,625,126; 5,569,825; 5,545,807; 5,545,806, and 5,591,669, the disclosures of which are incorporated herein by reference in their entireties. Such antibodies are typically monoclonal, and are typically produced using techniques developed for production of murine antibodies.

[0273] Human antibodies are particularly useful, and often preferred, when the antibodies of the present invention are to be administered to human beings as in vivo diagnostic or therapeutic agents, since recipient immune response to the administered antibody will often be substantially less than that occasioned by administration of an antibody derived from another species, such as mouse.

[0274] IgG, IgM, IgD, IgE, IgY, and IgA antibodies of the present invention can also be obtained from other species, including mammals such as rodents (typically mouse, but also rat, guinea pig, and hamster) lagomorphs, typically rabbits, and also larger mammals, such as sheep, goats, cows, and horses, and other egg laying birds or reptiles such as chickens or alligators. For example, avian antibodies may be generated using techniques described in WO 00/29444, published May 25, 2000, the contents of which are hereby incorporated in their entirety. In such cases, as with the transgenic human-antibody-producing non-human mammals, fortuitous immunization is not required, and the non-human mammal is typically affirmatively immunized, according to standard immunization protocols, with the protein or protein fragment of the present invention.

[0275] As discussed above, virtually all fragments of 8 or more contiguous amino acids of the proteins of the present invention can be used effectively as immunogens when conjugated to a carrier, typically a protein such as bovine thyroglobulin, keyhole limpet hemocyanin, or bovine serum albumin, conveniently using a bifunctional linker such as those described elsewhere above, which discussion is incorporated by reference here.

[0276] Immunogenicity can also be conferred by fusion of the polypeptide and fragments of the present invention to other moieties. For example, peptides of the present invention can be produced by solid phase synthesis on a branched polylysine core matrix; these multiple antigenic peptides (MAPs) provide high purity, increased avidity, accurate chemical definition and improved safety in vaccine development. Tam et al., Proc. Natl. Acad. Sci. USA 85: 5409-5413 (1988); Posnett et al., J. Biol. Chem. 263: 1719-1725 (1988).

[0277] Protocols for immunizing non-human mammals or avian species are well-established in the art. See Harlow et al. (eds.), Using Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory (1998); Coligan et al. (eds.), Current Protocols in Immunology, John Wiley & Sons, Inc. (2001); Zola, Monoclonal Antibodies: Preparation and Use of Monoclonal Antibodies and Engineered Antibody Derivatives (Basics: From Background to Bench), Springer Verlag (2000); Gross M, Speck J.Dtsch. Tierarztl. Wochenschr. 103: 417-422 (1996), the disclosures of which are incorporated herein by reference. Immunization protocols often include multiple immunizations, either with or without adjuvants such as Freund's complete adjuvant and Freund's incomplete adjuvant, and may include naked DNA immunization (Moss, Semin. Immunol. 2: 317-327 (1990).

[0278] Antibodies from non-human mammals and avian species can be polyclonal or monoclonal, with polyclonal antibodies having certain advantages in immunohistochemical detection of the proteins of the present invention and monoclonal antibodies having advantages in identifying and distinguishing particular epitopes of the proteins of the present invention. Antibodies from avian species may have particular advantage in detection of the proteins of the present invention, in human serum or tissues (Vikinge et al., Biosens. Bioelectron. 13: 1257-1262 (1998).

[0279] Following immunization, the antibodies of the present invention can be produced using any art-accepted technique. Such techniques are well-known in the art, Coligan, supra; Zola, supra; Howard et al. (eds.), Basic Methods in Antibody Production and Characterization, CRC Press (2000); Harlow, supra; Davis (ed.), Monoclonal Antibody Protocols, Vol. 45, Humana Press (1995); Delves (ed.), Antibody Production: Essential Techniques, John Wiley & Son Ltd (1997); Kenney, Antibody Solution: An Antibody Methods Manual, Chapman & Hall (1997), incorporated herein by reference in their entireties, and thus need not be detailed here.

[0280] Briefly, however, such techniques include, inter alia, production of monoclonal antibodies by hybridomas and expression of antibodies or fragments or derivatives thereof from host cells engineered to express immunoglobulin genes or fragments thereof. These two methods of production are not mutually exclusive: genes encoding antibodies specific for the proteins or protein fragments of the present invention can be cloned from hybridomas and thereafter expressed in other host cells. Nor need the two necessarily be performed together: e.g., genes encoding antibodies specific for the proteins and protein fragments of the present invention can be cloned directly from B cells known to be specific for the desired protein, as further described in U.S Pat. No. 5,627,052, the disclosure of which is incorporated herein by reference in its entirety, or from antibody-displaying phage.

[0281] Recombinant expression in host cells is particularly useful when fragments or derivatives of the antibodies of the present invention are desired.

[0282] Host cells for recombinant production of either whole antibodies, antibody fragments, or antibody derivatives can be prokaryotic or eukaryotic.

[0283] Prokaryotic hosts are particularly useful for producing phage displayed antibodies of the present invention.

[0284] The technology of phage-displayed antibodies, in which antibody variable region fragments are fused, for example, to the gene III protein (pIII) or gene VIII protein (pVIII) for display on the surface of filamentous phage, such as M13, is by now well-established. See, e.g., Sidhu, Curr. Opin. Biotechnol. 11(6): 610-6 (2000); Griffiths et al., Curr. Opin. Biotechnol. 9(1): 102-8 (1998); Hoogenboom et al., Immunotechnology, 4(1): 1-20 (1998); Rader et al., Current Opinion in Biotechnology 8: 503-508 (1997); Aujame et al., Human Antibodies 8: 155-168 (1997); Hoogenboom, Trends in Biotechnol. 15: 62-70 (1997); de Kruif et al., 17: 453-455 (1996); Barbas et al., Trends in Biotechnol. 14: 230-234 (1996); Winter et al., Ann. Rev. Immunol. 433-455 (1994). Techniques and protocols required to generate, propagate, screen (pan), and use the antibody fragments from such libraries have recently been compiled. See, e.g., Barbas (2001), supra; Kay, supra; Abelson, supra, the disclosures of which are incorporated herein by reference in their entireties.

[0285] Typically, phage-displayed antibody fragments are scFv fragments or Fab fragments; when desired, full length antibodies can be produced by cloning the variable regions from the displaying phage into a complete antibody and expressing the full length antibody in a further prokaryotic or a eukaryotic host cell.

[0286] Eukaryotic cells are also useful for expression of the antibodies, antibody fragments, and antibody derivatives of the present invention.

[0287] For example, antibody fragments of the present invention can be produced in Pichia pastoris and in Saccharomyces cerevisiae. See, e.g., Takahashi et al., Biosci. Biotechnol. Biochem. 64(10): 2138-44 (2000); Freyre et al., J. Biotechnol. 76(2-3):1 57-63 (2000); Fischer et al., Biotechnol. Appl. Biochem. 30 (Pt 2): 117-20 (1999); Pennell et al., Res. Immunol. 149(6): 599-603 (1998); Eldin et al., J. Immunol. Methods. 201(1): 67-75 (1997);, Frenken et al., Res. Immunol. 149(6): 589-99 (1998); Shusta et al., Nature Biotechnol. 16(8): 773-7 (1998), the disclosures of which are incorporated herein by reference in their entireties.

[0288] Antibodies, including antibody fragments and derivatives, of the present invention can also be produced in insect cells. See, e.g., Li et al., Protein Expr. Purif. 21(1): 121-8 (2001); Ailor et al., Biotechnol. Bioeng. 58(2-3): 196-203 (1998); Hsu et al., Biotechnol. Prog. 13(1): 96-104 (1997); Edelman et al., Immunology 91(1): 13-9 (1997); and Nesbit et al., J. Immunol. Methods 151(1-2): 201-8 (1992), the disclosures of which are incorporated herein by reference in their entireties.

[0289] Antibodies and fragments and derivatives thereof of the present invention can also be produced in plant cells, particularly maize or tobacco, Giddings et al., Nature Biotechnol. 18(11): 1151-5 (2000); Gavilondo et al., Biotechniques 29(1): 128-38 (2000); Fischer et al., J. Biol. Regul. Homeost. Agents 14(2): 83-92 (2000); Fischer et al., Biotechnol. Appl. Biochem. 30 (Pt 2): 113-6 (1999); Fischer et al., Biol. Chem. 380(7-8): 825-39 (1999); Russell, Curr. Top. Microbiol. Immunol. 240: 119-38 (1999); and Ma et al., Plant Physiol. 109(2): 341-6 (1995), the disclosures of which are incorporated herein by reference in their entireties.

[0290] Antibodies, including antibody fragments and derivatives, of the present invention can also be produced in transgenic, non-human, mammalian milk. See, e.g. Pollock et al., J. Immunol Methods. 231: 147-57 (1999); Young et al., Res. Immunol. 149: 609-10 (1998); Limonta et al., Immunotechnology 1: 107-13 (1995), the disclosures of which are incorporated herein by reference in their entireties.

[0291] Mammalian cells useful for recombinant expression of antibodies, antibody fragments, and antibody derivatives of the present invention include CHO cells, COS cells, 293 cells, and myeloma cells.

[0292] Verma et al., J. Immunol. Methods 216(1-2):165-81 (1998), herein incorporated by reference, review and compare bacterial, yeast, insect and mammalian expression systems for expression of antibodies.

[0293] Antibodies of the present invention can also be prepared by cell free translation, as further described in Merk et al., J. Biochem. (Tokyo) 125(2): 328-33 (1999) and Ryabova et al., Nature Biotechnol. 15(1): 79-84 (1997), and in the milk of transgenic animals, as further described in Pollock et al., J. Immunol. Methods 231(1-2): 147-57 (1999), the disclosures of which are incorporated herein by reference in their entireties.

[0294] The invention further provides antibody fragments that bind specifically to one or more of the proteins and protein fragments of the present invention, to one or more of the proteins and protein fragments encoded by the isolated nucleic acids of the present invention, or the binding of which can be competitively inhibited by one or more of the proteins and protein fragments of the present invention or one or more of the proteins and protein fragments encoded by the isolated nucleic acids of the present invention.

[0295] Among such useful fragments are Fab, Fab′, Fv, F(ab)′₂, and single chain Fv (scFv) fragments. Other useful fragments are described in Hudson, Curr. Opin. Biotechnol. 9(4): 395-402 (1998).

[0296] It is also an aspect of the present invention to provide antibody derivatives that bind specifically to one or more of the proteins and protein fragments of the present invention, to one or more of the proteins and protein fragments encoded by the isolated nucleic acids of the present invention, or the binding of which can be competitively inhibited by one or more of the proteins and protein fragments of the present invention or one or more of the proteins and protein fragments encoded by the isolated nucleic acids of the present invention.

[0297] Among such useful derivatives are chimeric, primatized, and humanized antibodies; such derivatives are less immunogenic in human beings, and thus more suitable for in vivo administration, than are unmodified antibodies from non-human mammalian species. Another useful derivative is PEGylation to increase the serum half life of the antibodies.

[0298] Chimeric antibodies typically include heavy and/or light chain variable regions (including both CDR and framework residues) of immunoglobulins of one species, typically mouse, fused to constant regions of another species, typically human. See, e.g., U.S. Pat. No. 5,807,715; Morrison et al., Proc. Natl. Acad. Sci USA.81(21): 6851-5 (1984); Sharon et al., Nature 309(5966): 364-7 (1984); Takeda et al., Nature 314(6010): 452-4 (1985), the disclosures of which are incorporated herein by reference in their entireties. Primatized and humanized antibodies typically include heavy and/or light chain CDRs from a murine antibody grafted into a non-human primate or human antibody V region framework, usually further comprising a human constant region, Riechmann et al., Nature 332(6162): 323-7 (1988); Co et al., Nature 351(6326): 501-2 (1991); U.S. Pat. Nos. 6,054,297; 5,821,337; 5,770,196; 5,766,886; 5,821,123; 5,869,619; 6,180,377; 6,013,256; 5,693,761; and 6,180,370, the disclosures of which are incorporated herein by reference in their entireties.

[0299] Other useful antibody derivatives of the invention include heteromeric antibody complexes and antibody fusions, such as diabodies (bispecific antibodies), single-chain diabodies, and intrabodies.

[0300] It is contemplated that the nucleic acids encoding the antibodies of the present invention can be operably joined to other nucleic acids forming a recombinant vector for cloning or for expression of the antibodies of the invention. The present invention includes any recombinant vector containing the coding sequences, or part thereof, whether for eukaryotic transduction, transfection or gene therapy. Such vectors may be prepared using conventional molecular biology techniques, known to those with skill in the art, and would comprise DNA encoding sequences for the immunoglobulin V-regions including framework and CDRs or parts thereof, and a suitable promoter either with or without a signal sequence for intracellular transport. Such vectors may be transduced or transfected into eukaryotic cells or used for gene therapy (Marasco et al., Proc. Natl. Acad. Sci. (USA) 90: 7889-7893 (1993); Duan et al., Proc. Natl. Acad. Sci. (USA) 91: 5075-5079 (1994), by conventional techniques, known to those with skill in the art.

[0301] The antibodies of the present invention, including fragments and derivatives thereof, can usefully be labeled. It is, therefore, another aspect of the present invention to provide labeled antibodies that bind specifically to one or more of the proteins and protein fragments of the present invention, to one or more of the proteins and protein fragments encoded by the isolated nucleic acids of the present invention, or the binding of which can be competitively inhibited by one or more of the proteins and protein fragments of the present invention or one or more of the proteins and protein fragments encoded by the isolated nucleic acids of the present invention.

[0302] The choice of label depends, in part, upon the desired use.

[0303] For example, when the antibodies of the present invention are used for immunohistochemical staining of tissue samples, the label is preferably an enzyme that catalyzes production and local deposition of a detectable product.

[0304] Enzymes typically conjugated to antibodies to permit their immunohistochemical visualization are well-known, and include alkaline phosphatase, β-galactosidase, glucose oxidase, horseradish peroxidase (HRP), and urease. Typical substrates for production and deposition of visually detectable products include o-nitrophenyl-beta-D-galactopyranoside (ONPG); o-phenylenediamine dihydrochloride (OPD); p-nitrophenyl phosphate (PNPP); p-nitrophenyl-beta-D-galactopryanoside (PNPG); 3′,3′-diaminobenzidine (DAB); 3-amino-9-ethylcarbazole (AEC); 4-chloro-1-naphthol (CN); 5-bromo-4-chloro-3-indolyl-phosphate (BCIP); ABTS®; BluoGal; iodonitrotetrazolium (INT); nitroblue tetrazolium chloride (NBT); phenazine methosulfate (PMS); phenolphthalein monophosphate (PMP); tetramethyl benzidine (TMB); tetranitroblue tetrazolium (TNBT); X-Gal; X-Gluc; and X-Glucoside.

[0305] Other substrates can be used to produce products for local deposition that are luminescent. For example, in the presence of hydrogen peroxide (H₂O₂), horseradish peroxidase (HRP) can catalyze the oxidation of cyclic diacylhydrazides, such as luminol. Immediately following the oxidation, the luminol is in an excited state (intermediate reaction product), which decays to the ground state by emitting light. Strong enhancement of the light emission is produced by enhancers, such as phenolic compounds. Advantages include high sensitivity, high resolution, and rapid detection without radioactivity and requiring only small amounts of antibody. See, e.g., Thorpe et al., Methods Enzymol. 133: 331-53 (1986); Kricka et al., J. Immunoassay 17(1): 67-83 (1996); and Lundqvist et al., J. Biolumin. Chemilumin. 10(6): 353-9 (1995), the disclosures of which are incorporated herein by reference in their entireties. Kits for such enhanced chemiluminescent detection (ECL) are available commercially.

[0306] The antibodies can also be labeled using colloidal gold.

[0307] As another example, when the antibodies of the present invention are used, e.g., for flow cytometric detection, for scanning laser cytometric detection, or for fluorescent immunoassay, they can usefully be labeled with fluorophores.

[0308] There are a wide variety of fluorophore labels that can usefully be attached to the antibodies of the present invention.

[0309] For flow cytometric applications, both for extracellular detection and for intracellular detection, common useful fluorophores can be fluorescein isothiocyanate (FITC), allophycocyanin (APC), R-phycoerythrin (PE), peridinin chlorophyll protein (PerCP), Texas Red, Cy3, Cy5, fluorescence resonance energy tandem fluorophores such as PerCP-Cy5.5, PE-Cy5, PE-Cy5.5, PE-Cy7, PE-Texas Red, and APC-Cy7.

[0310] Other fluorophores include, inter alia, Alexa Fluor® 350, Alexa Fluor® 488, Alexa Fluor® 532, Alexa Fluor® 546, Alexa Fluor® 568, Alexa Fluor® 594, Alexa Fluor® 647 (monoclonal antibody labeling kits available from Molecular Probes, Inc., Eugene, Oreg., USA), BODIPY dyes, such as BODIPY 493/503, BODIPY FL, BODIPY R6G, BODIPY 530/550, BODIPY TMR, BODIPY 558/568, BODIPY 558/568, BODIPY 564/570, BODIPY 576/589, BODIPY 581/591, BODIPY TR, BODIPY 630/650, BODIPY 650/665, Cascade Blue, Cascade Yellow, Dansyl, lissamine rhodamine B, Marina Blue, Oregon Green 488, Oregon Green 514, Pacific Blue, rhodamine 6G, rhodamine green, rhodamine red, tetramethylrhodamine, Texas Red (available from Molecular Probes, Inc., Eugene, Oreg., USA), and Cy2, Cy3, Cy3.5, Cy5, Cy5.5, Cy7, all of which are also useful for fluorescently labeling the antibodies of the present invention.

[0311] For secondary detection using labeled avidin, streptavidin, captavidin or neutravidin, the antibodies of the present invention can usefully be labeled with biotin.

[0312] When the antibodies of the present invention are used, e.g., for Western blotting applications, they can usefully be labeled with radioisotopes, such as ³³P, ³²P, ³⁵S, ³H, and ¹²⁵I.

[0313] As another example, when the antibodies of the present invention are used for radioimmunotherapy, the label can usefully be ²²⁸Th, ²²⁷Ac, ²²⁵Ac, ²²³Ra, ²¹³Bi, ²¹²Pb, ²¹²Bi, ²¹¹At, ²⁰³Pb, ¹⁹⁴Os, ¹⁸⁸Re, ¹⁸⁶Re, ¹⁵³Sm, ¹⁴⁹Tb, ¹³¹I, ¹²⁵I, ¹¹¹In, ¹⁰⁵Rh, ^(99m)Tc, ⁹⁷Ru, ⁹⁰Y, ⁹⁰Sr, ⁸⁸Y, ⁷²Se, ⁶⁷Cu, or ⁴⁷Sc.

[0314] As another example, when the antibodies of the present invention are to be used for in vivo diagnostic use, they can be rendered detectable by conjugation to MRI contrast agents, such as gadolinium diethylenetriaminepentaacetic acid (DTPA), Lauffer et al., Radiology 207(2): 529-38 (1998), or by radioisotopic labeling.

[0315] As would be understood, use of the labels described above is not restricted to the application for which they are mentioned.

[0316] The antibodies of the present invention, including fragments and derivatives thereof, can also be conjugated to toxins, in order to target the toxin's ablative action to cells that display and/or express the proteins of the present invention. Commonly, the antibody in such immunotoxins is conjugated to Pseudomonas exotoxin A, diphtheria toxin, shiga toxin A, anthrax toxin lethal factor, or ricin. See Hall (ed.), Immunotoxin Methods and Protocols (Methods in Molecular Biology, vol. 166), Humana Press (2000); and Frankel et al. (eds.), Clinical Applications of Immunotoxins, Springer-Verlag (1998), the disclosures of which are incorporated herein by reference in their entireties.

[0317] The antibodies of the present invention can usefully be attached to a substrate, and it is, therefore, another aspect of the invention to provide antibodies that bind specifically to one or more of the proteins and protein fragments of the present invention, to one or more of the proteins and protein fragments encoded by the isolated nucleic acids of the present invention, or the binding of which can be competitively inhibited by one or more of the proteins and protein fragments of the present invention or one or more of the proteins and protein fragments encoded by the isolated nucleic acids of the present invention, attached to a substrate.

[0318] Substrates can be porous or nonporous, planar or non-planar.

[0319] For example, the antibodies of the present invention can usefully be conjugated to filtration media, such as NHS-activated Sepharose or CNBr-activated Sepharose for purposes of immunoaffinity chromatography.

[0320] For example, the antibodies of the present invention can usefully be attached to paramagnetic microspheres, typically by biotin-streptavidin interaction, which microspheres can then be used for isolation of cells that express or display the proteins of the present invention. As another example, the antibodies of the present invention can usefully be attached to the surface of a microtiter plate for ELISA.

[0321] As noted above, the antibodies of the present invention can be produced in prokaryotic and eukaryotic cells. It is, therefore, another aspect of the present invention to provide cells that express the antibodies of the present invention, including hybridoma cells, B cells, plasma cells, and host cells recombinantly modified to express the antibodies of the present invention.

[0322] In yet a further aspect, the present invention provides aptamers evolved to bind specifically to one or more of the proteins and protein fragments of the present invention, to one or more of the proteins and protein fragments encoded by the isolated nucleic acids of the present invention, or the binding of which can be competitively inhibited by one or more of the proteins and protein fragments of the present invention or one or more of the proteins and protein fragments encoded by the isolated nucleic acids of the present invention.

[0323] In sum, one of skill in the art, provided with the teachings of this invention, has available a variety of methods which may be used to alter the biological properties of the antibodies of this invention including methods which would increase or decrease the stability or half-life, immunogenicity, toxicity, affinity or yield of a given antibody molecule, or to alter it in any other way that may render it more suitable for a particular application.

[0324] Transgenic Animals and Cells

[0325] In another aspect, the invention provides transgenic cells and non-human organisms comprising nucleic acid molecules of the invention. In a preferred embodiment, the transgenic cells and non-human organisms comprise a nucleic acid molecule encoding a BSP. In a preferred embodiment, the BSP comprises an amino acid sequence selected from SEQ ID NO: 172 through 295, or a fragment, mutein, homologous protein or allelic variant thereof. In another preferred embodiment, the transgenic cells and non-human organism comprise a BSNA of the invention, preferably a BSNA comprising a nucleotide sequence selected from the group consisting of SEQ ID NO: 1 through 171, or a part, substantially similar nucleic acid molecule, allelic variant or hybridizing nucleic acid molecule thereof.

[0326] In another embodiment, the transgenic cells and non-human organisms have a targeted disruption or replacement of the endogenous orthologue of the human BSG. The transgenic cells can be embryonic stem cells or somatic cells. The transgenic non-human organisms can be chimeric, nonchimeric heterozygotes, and nonchimeric homozygotes. Methods of producing transgenic animals are well-known in the art. See, e.g., Hogan et al., Manipulating the Mouse Embryo: A Laboratory Manual, 2d ed., Cold Spring Harbor Press (1999); Jackson et al., Mouse Genetics and Transgenics: A Practical Approach, Oxford University Press (2000); and Pinkert, Transgenic Animal Technology: A Laboratory Handbook, Academic Press (1999).

[0327] Any technique known in the art may be used to introduce a nucleic acid molecule of the invention into an animal to produce the founder lines of transgenic animals. Such techniques include, but are not limited to, pronuclear microinjection. (see, e.g., Paterson et al., Appl. Microbiol. Biotechnol. 40: 691-698 (1994); Carver et al., Biotechnology 11: 1263-1270 (1993); Wright et al., Biotechnology 9: 830-834 (1991); and U.S. Pat. No. 4,873,191 (1989 retrovirus-mediated gene transfer into germ lines, blastocysts or embryos (see, e.g., Van der Putten et al., Proc. Natl. Acad. Sci., USA 82: 6148-6152 (1985)); gene targeting in embryonic stem cells (see, e.g., Thompson et al., Cell 56: 313-321 (1989)); electroporation of cells or embryos (see, e.g., Lo, 1983, Mol. Cell. Biol. 3: 1803-1814 (1983)); introduction using a gene gun (see, e.g., Ulmer et al., Science 259: 1745-49 (1993); introducing nucleic acid constructs into embryonic pleuripotent stem cells and transferring the stem cells back into the blastocyst; and sperm-mediated gene transfer (see, e.g., Lavitrano et al., Cell 57: 717-723 (1989)).

[0328] Other techniques include, for example, nuclear transfer into enucleated oocytes of nuclei from cultured embryonic, fetal, or adult cells induced to quiescence (see, e.g., Campell et al., Nature 380: 64-66 (1996); Wilmut et al., Nature 385: 810-813 (1997)). The present invention provides for transgenic animals that carry the transgene (i.e., a nucleic acid molecule of the invention) in all their cells, as well as animals which carry the transgene in some, but not all their cells, i.e., mosaic animals or chimeric animals.

[0329] The transgene may be integrated as a single transgene or as multiple copies, such as in concatamers, e.g., head-to-head tandems or head-to-tail tandems. The transgene may also be selectively introduced into and activated in a particular cell type by following, e.g., the teaching of Lasko et al. et al., Proc. Natl. Acad. Sci. USA 89: 6232-6236 (1992). The regulatory sequences required for such a cell-type specific activation will depend upon the particular cell type of interest, and will be apparent to those of skill in the art.

[0330] Once transgenic animals have been generated, the expression of the recombinant gene may be assayed utilizing standard techniques. Initial screening may be accomplished by Southern blot analysis or PCR techniques to analyze animal tissues to verify that integration of the transgene has taken place. The level of mRNA expression of the transgene in the tissues of the transgenic animals may also be assessed using techniques which include, but are not limited to, Northern blot analysis of tissue samples obtained from the animal, in situ hybridization analysis, and reverse transcriptase-PCR (RT-PCR). Samples of transgenic gene-expressing tissue may also be evaluated immunocytochemically or immunohistochemically using antibodies specific for the transgene product.

[0331] Once the founder animals are produced, they may be bred, inbred, outbred, or crossbred to produce colonies of the particular animal. Examples of such breeding strategies include, but are not limited to: outbreeding of founder animals with more than one integration site in order to establish separate lines; inbreeding of separate lines in order to produce compound transgenics that express the transgene at higher levels because of the effects of additive expression of each transgene; crossing of heterozygous transgenic animals to produce animals homozygous for a given integration site in order to both augment expression and eliminate the need for screening of animals by DNA analysis; crossing of separate homozygous lines to produce compound heterozygous or homozygous lines; and breeding to place the transgene on a distinct background that is appropriate for an experimental model of interest.

[0332] Transgenic animals of the invention have uses which include, but are not limited to, animal model systems useful in elaborating the biological function of polypeptides of the present invention, studying conditions and/or disorders associated with aberrant expression, and in screening for compounds effective in ameliorating such conditions and/or disorders.

[0333] Methods for creating a transgenic animal with a disruption of a targeted gene are also well-known in the art. In general, a vector is designed to comprise some nucleotide sequences homologous to the endogenous targeted gene. The vector is introduced into a cell so that it may integrate, via homologous recombination with chromosomal sequences, into the endogenous gene, thereby disrupting the function of the endogenous gene. The transgene may also be selectively introduced into a particular cell type, thus inactivating the endogenous gene in only that cell type. See, e.g., Gu et al., Science 265: 103-106 (1994). The regulatory sequences required for such a cell-type specific inactivation will depend upon the particular cell type of interest, and will be apparent to those of skill in the art. See, e.g., Smithies et al., Nature 317: 230-234 (1985); Thomas et al., Cell 51: 503-512 (1987); Thompson et al., Cell 5: 313-321 (1989).

[0334] In one embodiment, a mutant, non-functional nucleic acid molecule of the invention (or a completely unrelated DNA sequence) flanked by DNA homologous to the endogenous nucleic acid sequence (either the coding regions or regulatory regions of the gene) can be used, with or without a selectable marker and/or a negative selectable marker, to transfect cells that express polypeptides of the invention in vivo. In another embodiment, techniques known in the art are used to generate knockouts in cells that contain, but do not express the gene of interest. Insertion of the DNA construct, via targeted homologous recombination, results in inactivation of the targeted gene. Such approaches are particularly suited in research and agricultural fields where modifications to embryonic stem cells can be used to generate animal offspring with an inactive targeted gene. See, e.g., Thomas, supra and Thompson, supra. However this approach can be routinely adapted for use in humans provided the recombinant DNA constructs are directly administered or targeted to the required site in vivo using appropriate viral vectors that will be apparent to those of skill in the art.

[0335] In further embodiments of the invention, cells that are genetically engineered to express the polypeptides of the invention, or alternatively, that are genetically engineered not to express the polypeptides of the invention (e.g., knockouts) are administered to a patient in vivo. Such cells may be obtained from an animal or patient or an MHC compatible donor and can include, but are not limited to fibroblasts, bone marrow cells, blood cells (e.g., lymphocytes), adipocytes, muscle cells, endothelial cells etc. The cells are genetically engineered in vitro using recombinant DNA techniques to introduce the coding sequence of polypeptides of the invention into the cells, or alternatively, to disrupt the coding sequence and/or endogenous regulatory sequence associated with the polypeptides of the invention, e.g., by transduction (using viral vectors, and preferably vectors that integrate the transgene into the cell genome) or transfection procedures, including, but not limited to, the use of plasmids, cosmids, YACs, naked DNA, electroporation, liposomes, etc.

[0336] The coding sequence of the polypeptides of the invention can be placed under the control of a strong constitutive or inducible promoter or promoter/enhancer to achieve expression, and preferably secretion, of the polypeptides of the invention. The engineered cells which express and preferably secrete the polypeptides of the invention can be introduced into the patient systemically, e.g., in the circulation, or intraperitoneally.

[0337] Alternatively, the cells can be incorporated into a matrix and implanted in the body, e.g., genetically engineered fibroblasts can be implanted as part of a skin graft; genetically engineered endothelial cells can be implanted as part of a lymphatic or vascular graft. See, e.g., U.S. Pat. Nos. 5,399,349 and 5,460,959, each of which is incorporated by reference herein in its entirety.

[0338] When the cells to be administered are non-autologous or non-MHC compatible cells, they can be administered using well-known techniques which prevent the development of a host immune response against the introduced cells. For example, the cells may be introduced in an encapsulated form which, while allowing for an exchange of components with the immediate extracellular environment, does not allow the introduced cells to be recognized by the host immune system.

[0339] Transgenic and “knock-out” animals of the invention have uses which include, but are not limited to, animal model systems useful in elaborating the biological function of polypeptides of the present invention, studying conditions and/or disorders associated with aberrant expression, and in screening for compounds effective in ameliorating such conditions and/or disorders.

[0340] Computer Readable Means

[0341] A further aspect of the invention relates to a computer readable means for storing the nucleic acid and amino acid sequences of the instant invention. In a preferred embodiment, the invention provides a computer readable means for storing SEQ ID NO: 1 through 171 and SEQ ID NO: 172 through 295 as described herein, as the complete set of sequences or in any combination. The records of the computer readable means can be accessed for reading and display and for interface with a computer system for the application of programs allowing for the location of data upon a query for data meeting certain criteria, the comparison of sequences, the alignment or ordering of sequences meeting a set of criteria, and the like.

[0342] The nucleic acid and amino acid sequences of the invention are particularly useful as components in databases useful for search analyses as well as in sequence analysis algorithms. As used herein, the terms “nucleic acid sequences of the invention” and “amino acid sequences of the invention” mean any detectable chemical or physical characteristic of a polynucleotide or polypeptide of the invention that is or may be reduced to or stored in a computer readable form. These include, without limitation, chromatographic scan data or peak data, photographic data or scan data therefrom, and mass spectrographic data.

[0343] This invention provides computer readable media having stored thereon sequences of the invention. A computer readable medium may comprise one or more of the following: a nucleic acid sequence comprising a sequence of a nucleic acid sequence of the invention; an amino acid sequence comprising an amino acid sequence of the invention; a set of nucleic acid sequences wherein at least one of said sequences comprises the sequence of a nucleic acid sequence of the invention; a set of amino acid sequences wherein at least one of said sequences comprises the sequence of an amino acid sequence of the invention; a data set representing a nucleic acid sequence comprising the sequence of one or more nucleic acid sequences of the invention; a data set representing a nucleic acid sequence encoding an amino acid sequence comprising the sequence of an amino acid sequence of the invention; a set of nucleic acid sequences wherein at least one of said sequences comprises the sequence of a nucleic acid sequence of the invention; a set of amino acid sequences wherein at least one of said sequences comprises the sequence of an amino acid sequence of the invention; a data set representing a nucleic acid sequence comprising the sequence of a nucleic acid sequence of the invention; a data set representing a nucleic acid sequence encoding an amino acid sequence comprising the sequence of an amino acid sequence of the invention. The computer readable medium can be any composition of matter used to store information or data, including, for example, commercially available floppy disks, tapes, hard drives, compact disks, and video disks.

[0344] Also provided by the invention are methods for the analysis of character sequences, particularly genetic sequences. Preferred methods of sequence analysis include, for example, methods of sequence homology analysis, such as identity and similarity analysis, RNA structure analysis, sequence assembly, cladistic analysis, sequence motif analysis, open reading frame determination, nucleic acid base calling, and sequencing chromatogram peak analysis.

[0345] A computer-based method is provided for performing nucleic acid sequence identity or similarity identification. This method comprises the steps of providing a nucleic acid sequence comprising the sequence of a nucleic acid of the invention in a computer readable medium; and comparing said nucleic acid sequence to at least one nucleic acid or amino acid sequence to identify sequence identity or similarity.

[0346] A computer-based method is also provided for performing amino acid homology identification, said method comprising the steps of: providing an amino acid sequence comprising the sequence of an amino acid of the invention in a computer readable medium; and comparing said an amino acid sequence to at least one nucleic acid or an amino acid sequence to identify homology.

[0347] A computer-based method is still further provided for assembly of overlapping nucleic acid sequences into a single nucleic acid sequence, said method comprising the steps of: providing a first nucleic acid sequence comprising the sequence of a nucleic acid of the invention in a computer readable medium; and screening for at least one overlapping region between said first nucleic acid sequence and a second nucleic acid sequence.

[0348] Diagnostic Methods for Breast Cancer

[0349] The present invention also relates to quantitative and qualitative diagnostic assays and methods for detecting, diagnosing, monitoring, staging and predicting cancers by comparing expression of a BSNA or a BSP in a human patient that has or may have breast cancer, or who is at risk of developing breast cancer, with the expression of a BSNA or a BSP in a normal human control. For purposes of the present invention, “expression of a BSNA” or “BSNA expression” means the quantity of BSG mRNA that can be measured by any method known in the art or the level of transcription that can be measured by any method known in the art in a cell, tissue, organ or whole patient. Similarly, the term “expression of a BSP” or “BSP expression” means the amount of BSP that can be measured by any method known in the art or the level of translation of a BSG BSNA that can be measured by any method known in the art.

[0350] The present invention provides methods for diagnosing breast cancer in a patient, in particular squamous cell carcinoma, by analyzing for changes in levels of BSNA or BSP in cells, tissues, organs or bodily fluids compared with levels of BSNA or BSP in cells, tissues, organs or bodily fluids of preferably the same type from a normal human control, wherein an increase, or decrease in certain cases, in levels of a BSNA or BSP in the patient versus the normal human control is associated with the presence of breast cancer or with a predilection to the disease. In another preferred embodiment, the present invention provides methods for diagnosing breast cancer in a patient by analyzing changes in the structure of the mRNA of a BSG compared to the mRNA from a normal control. These changes include, without limitation, aberrant splicing, alterations in polyadenylation and/or alterations in 5′ nucleotide capping. In yet another preferred embodiment, the present invention provides methods for diagnosing breast cancer in a patient by analyzing changes in a BSP compared to a BSP from a normal control. These changes include, e.g., alterations in glycosylation and/or phosphorylation of the BSP or subcellular BSP localization.

[0351] In a preferred embodiment, the expression of a BSNA is measured by determining the amount of an mRNA that encodes an amino acid sequence selected from SEQ ID NO: 172 through 295, a homolog, an allelic variant, or a fragment thereof. In a more preferred embodiment, the BSNA expression that is measured is the level of expression of a BSNA mRNA selected from SEQ ID NO: 1 through 171, or a hybridizing nucleic acid, homologous nucleic acid or allelic variant thereof, or a part of any of these nucleic acids. BSNA expression may be measured by any method known in the art, such as those described supra, including measuring mRNA expression by Northern blot, quantitative or qualitative reverse transcriptase PCR (RT-PCR), microarray, dot or slot blots or in situ hybridization. See, e.g., Ausubel (1992), supra; Ausubel (1999), supra; Sambrook (1989), supra; and Sambrook (2001), supra. BSNA transcription may be measured by any method known in the art including using a reporter gene hooked up to the promoter of a BSG of interest or doing nuclear run-off assays. Alterations in mRNA structure, e.g., aberrant splicing variants, may be determined by any method known in the art, including, RT-PCR followed by sequencing or restriction analysis. As necessary, BSNA expression may be compared to a known control, such as normal breast nucleic acid, to detect a change in expression.

[0352] In another preferred embodiment, the expression of a BSP is measured by determining the level of a BSP having an amino acid sequence selected from the group consisting of SEQ ID NO: 172 through 295, a homolog, an allelic variant, or a fragment thereof. Such levels are preferably determined in at least one of cells, tissues, organs and/or bodily fluids, including determination of normal and abnormal levels. Thus, for instance, a diagnostic assay in accordance with the invention for diagnosing over- or underexpression of BSNA or BSP compared to normal control bodily fluids, cells, or tissue samples may be used to diagnose the presence of breast cancer. The expression level of a BSP may be determined by any method known in the art, such as those described supra. In a preferred embodiment, the BSP expression level may be determined by radioimmunoassays, competitive-binding assays, ELISA, Western blot, FACS, immunohistochemistry, immunoprecipitation, proteomic approaches: two-dimensional gel electrophoresis (2D electrophoresis) and non-gel-based approaches such as mass spectrometry or protein interaction profiling. See, e.g, Harlow (1999), supra; Ausubel (1992), supra; and Ausubel (1999), supra. Alterations in the BSP structure may be determined by any method known in the art, including, e.g., using antibodies that specifically recognize phosphoserine, phosphothreonine or phosphotyrosine residues, two-dimensional polyacrylamide gel electrophoresis (2D PAGE) and/or chemical analysis of amino acid residues of the protein. Id.

[0353] In a preferred embodiment, a radioimmunoassay (RIA) or an ELISA is used. An antibody specific to a BSP is prepared if one is not already available. In a preferred embodiment, the antibody is a monoclonal antibody. The anti-BSP antibody is bound to a solid support and any free protein binding sites on the solid support are blocked with a protein such as bovine serum albumin. A sample of interest is incubated with the antibody on the solid support under conditions in which the BSP will bind to the anti-BSP antibody. The sample is removed, the solid support is washed to remove unbound material, and an anti-BSP antibody that is linked to a detectable reagent (a radioactive substance for RIA and an enzyme for ELISA) is added to the solid support and incubated under conditions in which binding of the BSP to the labeled antibody will occur. After binding, the unbound labeled antibody is removed by washing. For an ELISA, one or more substrates are added to produce a colored reaction product that is based upon the amount of a BSP in the sample. For an RIA, the solid support is counted for radioactive decay signals by any method known in the art. Quantitative results for both RIA and ELISA typically are obtained by reference to a standard curve.

[0354] Other methods to measure BSP levels are known in the art. For instance, a competition assay may be employed wherein an anti-BSP antibody is attached to a solid support and an allocated amount of a labeled BSP and a sample of interest are incubated with the solid support. The amount of labeled BSP detected which is attached to the solid support can be correlated to the quantity of a BSP in the sample.

[0355] Of the proteomic approaches, 2D PAGE is a well-known technique. Isolation of individual proteins from a sample such as serum is accomplished using sequential separation of proteins by isoelectric point and molecular weight. Typically, polypeptides are first separated by isoelectric point (the first dimension) and then separated by size using an electric current (the second dimension). In general, the second dimension is perpendicular to the first dimension. Because no two proteins with different sequences are identical on the basis of both size and charge, the result of 2D PAGE is a roughly square gel in which each protein occupies a unique spot. Analysis of the spots with chemical or antibody probes, or subsequent protein microsequencing can reveal the relative abundance of a given protein and the identity of the proteins in the sample.

[0356] Expression levels of a BSNA can be determined by any method known in the art, including PCR and other nucleic acid methods, such as ligase chain reaction (LCR) and nucleic acid sequence based amplification (NASBA), can be used to detect malignant cells for diagnosis and monitoring of various malignancies. For example, reverse-transcriptase PCR (RT-PCR) is a powerful technique which can be used to detect the presence of a specific mRNA population in a complex mixture of thousands of other mRNA species. In RT-PCR, an mRNA species is first reverse transcribed to complementary DNA (cDNA) with use of the enzyme reverse transcriptase; the cDNA is then amplified as in a standard PCR reaction.

[0357] Hybridization to specific DNA molecules (e.g., oligonucleotides) arrayed on a solid support can be used to both detect the expression of and quantitate the level of expression of one or more BSNAs of interest. In this approach, all or a portion of one or more BSNAs is fixed to a substrate. A sample of interest, which may comprise RNA, e.g., total RNA or polyA-selected mRNA, or a complementary DNA (cDNA) copy of the RNA is incubated with the solid support under conditions in which hybridization will occur between the DNA on the solid support and the nucleic acid molecules in the sample of interest. Hybridization between the substrate-bound DNA and the nucleic acid molecules in the sample can be detected and quantitated by several means, including, without limitation, radioactive labeling or fluorescent labeling of the nucleic acid molecule or a secondary molecule designed to detect the hybrid.

[0358] The above tests can be carried out on samples derived from a variety of cells, bodily fluids and/or tissue extracts such as homogenates or solubilized tissue obtained from a patient. Tissue extracts are obtained routinely from tissue biopsy and autopsy material. Bodily fluids useful in the present invention include blood, urine, saliva or any other bodily secretion or derivative thereof. By blood it is meant to include whole blood, plasma, serum or any derivative of blood. In a preferred embodiment, the specimen tested for expression of BSNA or BSP includes, without limitation, breast tissue, fluid obtained by bronchial alveolar lavage (BAL), sputum, breast cells grown in cell culture, blood, serum, lymph node tissue and lymphatic fluid. In another preferred embodiment, especially when metastasis of a primary breast cancer is known or suspected, specimens include, without limitation, tissues from brain, bone, bone marrow, liver, adrenal glands and colon. In general, the tissues may be sampled by biopsy, including, without limitation, needle biopsy, e.g., transthoracic needle aspiration, cervical mediatinoscopy, endoscopic lymph node biopsy, video-assisted thoracoscopy, exploratory thoracotomy, bone marrow biopsy and bone marrow aspiration. See Scott, supra and Franklin, pp. 529-570, in Kane, supra. For early and inexpensive detection, assaying for changes in BSNAs or BSPs in cells in sputum samples may be particularly useful. Methods of obtaining and analyzing sputum samples is disclosed in Franklin, supra.

[0359] All the methods of the present invention may optionally include determining the expression levels of one or more other cancer markers in addition to determining the expression level of a BSNA or BSP. In many cases, the use of another cancer marker will decrease the likelihood of false positives or false negatives. In one embodiment, the one or more other cancer markers include other BSNA or BSPs as disclosed herein. Other cancer markers useful in the present invention will depend on the cancer being tested and are known to those of skill in the art. In a preferred embodiment, at least one other cancer marker in addition to a particular BSNA or BSP is measured. In a more preferred embodiment, at least two other additional cancer markers are used. In an even more preferred embodiment, at least three, more preferably at least five, even more preferably at least ten additional cancer markers are used.

[0360] Diagnosing

[0361] In one aspect, the invention provides a method for determining the expression levels and/or structural alterations of one or more BSNAs and/or BSPs in a sample from a patient suspected of having breast cancer. In general, the method comprises the steps of obtaining the sample from the patient, determining the expression level or structural alterations of a BSNA and/or BSP and then ascertaining whether the patient has breast cancer from the expression level of the BSNA or BSP. In general, if high expression relative to a control of a BSNA or BSP is indicative of breast cancer, a diagnostic assay is considered positive if the level of expression of the BSNA or BSP is at least two times higher, and more preferably are at least five times higher, even more preferably at least ten times higher, than in preferably the same cells, tissues or bodily fluid of a normal human control. In contrast, if low expression relative to a control of a BSNA or BSP is indicative of breast cancer, a diagnostic assay is considered positive if the level of expression of the BSNA or BSP is at least two times lower, more preferably are at least five times lower, even more preferably at least ten times lower than in preferably the same cells, tissues or bodily fluid of a normal human control. The normal human control may be from a different patient or from uninvolved tissue of the same patient.

[0362] The present invention also provides a method of determining whether breast cancer has metastasized in a patient. One may identify whether the breast cancer has metastasized by measuring the expression levels and/or structural alterations of one or more BSNAs and/or BSPs in a variety of tissues. The presence of a BSNA or BSP in a certain tissue at levels higher than that of corresponding noncancerous tissue (e.g., the same tissue from another individual) is indicative of metastasis if high level expression of a BSNA or BSP is associated with breast cancer. Similarly, the presence of a BSNA or BSP in a tissue at levels lower than that of corresponding noncancerous tissue is indicative of metastasis if low level expression of a BSNA or BSP is associated with breast cancer. Further, the presence of a structurally altered BSNA or BSP that is associated with breast cancer is also indicative of metastasis.

[0363] In general, if high expression relative to a control of a BSNA or BSP is indicative of metastasis, an assay for metastasis is considered positive if the level of expression of the BSNA or BSP is at least two times higher, and more preferably are at least five times higher, even more preferably at least ten times higher, than in preferably the same cells, tissues or bodily fluid of a normal human control. In contrast, if low expression relative to a control of a BSNA or BSP is indicative of metastasis, an assay for metastasis is considered positive if the level of expression of the BSNA or BSP is at least two times lower, more preferably are at least five times lower, even more preferably at least ten times lower than in preferably the same cells, tissues or bodily fluid of a normal human control.

[0364] The BSNA or BSP of this invention may be used as element in an array or a multi-analyte test to recognize expression patterns associated with breast cancers or other breast related disorders. In addition, the sequences of either the nucleic acids or proteins may be used as elements in a computer program for pattern recognition of breast disorders.

[0365] Staging

[0366] The invention also provides a method of staging breast cancer in a human patient. The method comprises identifying a human patient having breast cancer and analyzing cells, tissues or bodily fluids from such human patient for expression levels and/or structural alterations of one or more BSNAs or BSPs. First, one or more tumors from a variety of patients are staged according to procedures well-known in the art, and the expression level of one or more BSNAs or BSPs is determined for each stage to obtain a standard expression level for each BSNA and BSP. Then, the BSNA or BSP expression levels are determined in a biological sample from a patient whose stage of cancer is not known. The BSNA or BSP expression levels from the patient are then compared to the standard expression level. By comparing the expression level of the BSNAs and BSPs from the patient to the standard expression levels, one may determine the stage of the tumor. The same procedure may be followed using structural alterations of a BSNA or BSP to determine the stage of a breast cancer.

[0367] Monitoring

[0368] Further provided is a method of monitoring breast cancer in a human patient. One may monitor a human patient to determine whether there has been metastasis and, if there has been, when metastasis began to occur. One may also monitor a human patient to determine whether a preneoplastic lesion has become cancerous. One may also monitor a human patient to determine whether a therapy, e.g., chemotherapy, radiotherapy or surgery, has decreased or eliminated the breast cancer. The method comprises identifying a human patient that one wants to monitor for breast cancer, periodically analyzing cells, tissues or bodily fluids from such human patient for expression levels of one or more BSNAs or BSPs, and comparing the BSNA or BSP levels over time to those BSNA or BSP expression levels obtained previously. Patients may also be monitored by measuring one or more structural alterations in a BSNA or BSP that are associated with breast cancer.

[0369] If increased expression of a BSNA or BSP is associated with metastasis, treatment failure, or conversion of a preneoplastic lesion to a cancerous lesion, then detecting an increase in the expression level of a BSNA or BSP indicates that the tumor is metastasizing, that treatment has failed or that the lesion is cancerous, respectively. One having ordinary skill in the art would recognize that if this were the case, then a decreased expression level would be indicative of no metastasis, effective therapy or failure to progress to a neoplastic lesion. If decreased expression of a BSNA or BSP is associated with metastasis, treatment failure, or conversion of a preneoplastic lesion to a cancerous lesion, then detecting an decrease in the expression level of a BSNA or BSP indicates that the tumor is metastasizing, that treatment has failed or that the lesion is cancerous, respectively. In a preferred embodiment, the levels of BSNAs or BSPs are determined from the same cell type, tissue or bodily fluid as prior patient samples. Monitoring a patient for onset of breast cancer metastasis is periodic and preferably is done on a quarterly basis, but may be done more or less frequently.

[0370] The methods described herein can further be utilized as prognostic assays to identify subjects having or at risk of developing a disease or disorder associated with increased or decreased expression levels of a BSNA and/or BSP. The present invention provides a method in which a test sample is obtained from a human patient and one or more BSNAs and/or BSPs are detected. The presence of higher (or lower) BSNA or BSP levels as compared to normal human controls is diagnostic for the human patient being at risk for developing cancer, particularly breast cancer. The effectiveness of therapeutic agents to decrease (or increase) expression or activity of one or more BSNAs and/or BSPs of the invention can also be monitored by analyzing levels of expression of the BSNAs and/or BSPs in a human patient in clinical trials or in in vitro screening assays such as in human cells. In this way, the gene expression pattern can serve as a marker, indicative of the physiological response of the human patient or cells, as the case may be, to the agent being tested.

[0371] Detection of Genetic Lesions or Mutations

[0372] The methods of the present invention can also be used to detect genetic lesions or mutations in a BSG, thereby determining if a human with the genetic lesion is susceptible to developing breast cancer or to determine what genetic lesions are responsible, or are partly responsible, for a person's existing breast cancer. Genetic lesions can be detected, for example, by ascertaining the existence of a deletion, insertion and/or substitution of one or more nucleotides from the BSGs of this invention, a chromosomal rearrangement of BSG, an aberrant modification of BSG (such as of the methylation pattern of the genomic DNA), or allelic loss of a BSG. Methods to detect such lesions in the BSG of this invention are known to those having ordinary skill in the art following the teachings of the specification.

[0373] Methods of Detecting Noncancerous Breast Diseases

[0374] The invention also provides a method for determining the expression levels and/or structural alterations of one or more BSNAs and/or BSPs in a sample from a patient suspected of having or known to have a noncancerous breast disease. In general, the method comprises the steps of obtaining a sample from the patient, determining the expression level or structural alterations of a BSNA and/or BSP, comparing the expression level or structural alteration of the BSNA or BSP to a normal breast control, and then ascertaining whether the patient has a noncancerous breast disease. In general, if high expression relative to a control of a BSNA or BSP is indicative of a particular noncancerous breast disease, a diagnostic assay is considered positive if the level of expression of the BSNA or BSP is at least two times higher, and more preferably are at least five times higher, even more preferably at least ten times higher, than in preferably the same cells, tissues or bodily fluid of a normal human control. In contrast, if low expression relative to a control of a BSNA or BSP is indicative of a noncancerous breast disease, a diagnostic assay is considered positive if the level of expression of the BSNA or BSP is at least two times lower, more preferably are at least five times lower, even more preferably at least ten times lower than in preferably the same cells, tissues or bodily fluid of a normal human control. The normal human control may be from a different patient or from uninvolved tissue of the same patient.

[0375] One having ordinary skill in the art may determine whether a BSNA and/or BSP is associated with a particular noncancerous breast disease by obtaining breast tissue from a patient having a noncancerous breast disease of interest and determining which BSNAs and/or BSPs are expressed in the tissue at either a higher or a lower level than in normal breast tissue. In another embodiment, one may determine whether a BSNA or BSP exhibits structural alterations in a particular noncancerous breast disease state by obtaining breast tissue from a patient having a noncancerous breast disease of interest and determining the structural alterations in one or more BSNAs and/or BSPs relative to normal breast tissue.

[0376] Methods for Identifying Breast Tissue

[0377] In another aspect, the invention provides methods for identifying breast tissue. These methods are particularly useful in, e.g., forensic science, breast cell differentiation and development, and in tissue engineering.

[0378] In one embodiment, the invention provides a method for determining whether a sample is breast tissue or has breast tissue-like characteristics. The method comprises the steps of providing a sample suspected of comprising breast tissue or having breast tissue-like characteristics, determining whether the sample expresses one or more BSNAs and/or BSPs, and, if the sample expresses one or more BSNAs and/or BSPs, concluding that the sample comprises breast tissue. In a preferred embodiment, the BSNA encodes a polypeptide having an amino acid sequence selected from SEQ ID NO: 172 through 295, or a homolog, allelic variant or fragment thereof. In a more preferred embodiment, the BSNA has a nucleotide sequence selected from SEQ ID NO: 1 through 171, or a hybridizing nucleic acid, an allelic variant or a part thereof Determining whether a sample expresses a BSNA can be accomplished by any method known in the art. Preferred methods include hybridization to microarrays, Northern blot hybridization, and quantitative or qualitative RT-PCR. In another preferred embodiment, the method can be practiced by determining whether a BSP is expressed. Determining whether a sample expresses a BSP can be accomplished by any method known in the art. Preferred methods include Western blot, ELISA, RIA and 2D PAGE. In one embodiment, the BSP has an amino acid sequence selected from SEQ ID NO: 172 through 295, or a homolog, allelic variant or fragment thereof. In another preferred embodiment, the expression of at least two BSNAs and/or BSPs is determined. In a more preferred embodiment, the expression of at least three, more preferably four and even more preferably five BSNAs and/or BSPs are determined.

[0379] In one embodiment, the method can be used to determine whether an unknown tissue is breast tissue. This is particularly useful in forensic science, in which small, damaged pieces of tissues that are not identifiable by microscopic or other means are recovered from a crime or accident scene. In another embodiment, the method can be used to determine whether a tissue is differentiating or developing into breast tissue. This is important in monitoring the effects of the addition of various agents to cell or tissue culture, e.g., in producing new breast tissue by tissue engineering. These agents include, e.g., growth and differentiation factors, extracellular matrix proteins and culture medium. Other factors that may be measured for effects on tissue development and differentiation include gene transfer into the cells or tissues, alterations in pH, aqueous:air interface and various other culture conditions.

[0380] Methods for Producing and Modifying Breast Tissue

[0381] In another aspect, the invention provides methods for producing engineered breast tissue or cells. In one embodiment, the method comprises the steps of providing cells, introducing a BSNA or a BSG into the cells, and growing the cells under conditions in which they exhibit one or more properties of breast tissue cells. In a preferred embodiment, the cells are pluripotent. As is well-known in the art, normal breast tissue comprises a large number of different cell types. Thus, in one embodiment, the engineered breast tissue or cells comprises one of these cell types. In another embodiment, the engineered breast tissue or cells comprises more than one breast cell type. Further, the culture conditions of the cells or tissue may require manipulation in order to achieve full differentiation and development of the breast cell tissue. Methods for manipulating culture conditions are well-known in the art.

[0382] Nucleic acid molecules encoding one or more BSPs are introduced into cells, preferably pluripotent cells. In a preferred embodiment, the nucleic acid molecules encode BSPs having amino acid sequences selected from SEQ ID NO: 172 through 295, or homologous proteins, analogs, allelic variants or fragments thereof. In a more preferred embodiment, the nucleic acid molecules have a nucleotide sequence selected from SEQ ID NO: 1 through 171, or hybridizing nucleic acids, allelic variants or parts thereof. In another highly preferred embodiment, a BSG is introduced into the cells. Expression vectors and methods of introducing nucleic acid molecules into cells are well-known in the art and are described in detail, supra.

[0383] Artificial breast tissue may be used to treat patients who have lost some or all of their breast function.

[0384] Pharmaceutical Compositions

[0385] In another aspect, the invention provides pharmaceutical compositions comprising the nucleic acid molecules, polypeptides, antibodies, antibody derivatives, antibody fragments, agonists, antagonists, and inhibitors of the present invention. In a preferred embodiment, the pharmaceutical composition comprises a BSNA or part thereof. In a more preferred embodiment, the BSNA has a nucleotide sequence selected from the group consisting of SEQ ID NO: 1 through 171, a nucleic acid that hybridizes thereto, an allelic variant thereof, or a nucleic acid that has substantial sequence identity thereto. In another preferred embodiment, the pharmaceutical composition comprises a BSP or fragment thereof. In a more preferred embodiment, the BSP having an amino acid sequence that is selected from the group consisting of SEQ ID NO: 172 through 295, a polypeptide that is homologous thereto, a fusion protein comprising all or a portion of the polypeptide, or an analog or derivative thereof. In another preferred embodiment, the pharmaceutical composition comprises an anti-BSP antibody, preferably an antibody that specifically binds to a BSP having an amino acid that is selected from the group consisting of SEQ ID NO: 172 through 295, or an antibody that binds to a polypeptide that is homologous thereto, a fusion protein comprising all or a portion of the polypeptide, or an analog or derivative thereof.

[0386] Such a composition typically contains from about 0.1 to 90% by weight of a therapeutic agent of the invention formulated in and/or with a pharmaceutically acceptable carrier or excipient.

[0387] Pharmaceutical formulation is a well-established art, and is further described in Gennaro (ed.), Remington: The Science and Practice of Pharmacy, 20^(th) ed., Lippincott, Williams & Wilkins (2000); Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, 7^(th) ed., Lippincott Williams & Wilkins (1999); and Kibbe (ed.), Handbook of Pharmaceutical Excipients American Pharmaceutical Association, 3^(rd) ed. (2000), the disclosures of which are incorporated herein by reference in their entireties, and thus need not be described in detail herein.

[0388] Briefly, formulation of the pharmaceutical compositions of the present invention will depend upon the route chosen for administration. The pharmaceutical compositions utilized in this invention can be administered by various routes including both enteral and parenteral routes, including oral, intravenous, intramuscular, subcutaneous, inhalation, topical, sublingual, rectal, intra-arterial, intramedullary, intrathecal, intraventricular, transmucosal, transdermal, intranasal, intraperitoneal, intrapulmonary, and intrauterine.

[0389] Oral dosage forms can be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, and the like, for ingestion by the patient.

[0390] Solid formulations of the compositions for oral administration can contain suitable carriers or excipients, such as carbohydrate or protein fillers, such as sugars, including lactose, sucrose, mannitol, or sorbitol; starch from corn, wheat, rice, potato, or other plants; cellulose, such as methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, or microcrystalline cellulose; gums including arabic and tragacanth; proteins such as gelatin and collagen; inorganics, such as kaolin, calcium carbonate, dicalcium phosphate, sodium chloride; and other agents such as acacia and alginic acid.

[0391] Agents that facilitate disintegration and/or solubilization can be added, such as the cross-linked polyvinyl pyrrolidone, agar, alginic acid, or a salt thereof, such as sodium alginate, microcrystalline cellulose, corn starch, sodium starch glycolate, and alginic acid.

[0392] Tablet binders that can be used include acacia, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone (Povidone™), hydroxypropyl methylcellulose, sucrose, starch and ethylcellulose.

[0393] Lubricants that can be used include magnesium stearates, stearic acid, silicone fluid, talc, waxes, oils, and colloidal silica.

[0394] Fillers, agents that facilitate disintegration and/or solubilization, tablet binders and lubricants, including the aforementioned, can be used singly or in combination.

[0395] Solid oral dosage forms need not be uniform throughout. For example, dragee cores can be used in conjunction with suitable coatings, such as concentrated sugar solutions, which can also contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.

[0396] Oral dosage forms of the present invention include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a coating, such as glycerol or sorbitol. Push-fit capsules can contain active ingredients mixed with a filler or binders, such as lactose or starches, lubricants, such as talc or magnesium stearate, and, optionally, stabilizers. In soft capsules, the active compounds can be dissolved or suspended in suitable liquids, such as fatty oils, liquid, or liquid polyethylene glycol with or without stabilizers.

[0397] Additionally, dyestuffs or pigments can be added to the tablets or dragee coatings for product identification or to characterize the quantity of active compound, i.e., dosage.

[0398] Liquid formulations of the pharmaceutical compositions for oral (enteral) administration are prepared in water or other aqueous vehicles and can contain various suspending agents such as methylcellulose, alginates, tragacanth, pectin, kelgin, carrageenan, acacia, polyvinylpyrrolidone, and polyvinyl alcohol. The liquid formulations can also include solutions, emulsions, syrups and elixirs containing, together with the active compound(s), wetting agents, sweeteners, and coloring and flavoring agents.

[0399] The pharmaceutical compositions of the present invention can also be formulated for parenteral administration. Formulations for parenteral administration can be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions.

[0400] For intravenous injection, water soluble versions of the compounds of the present invention are formulated in, or if provided as a lyophilate, mixed with, a physiologically acceptable fluid vehicle, such as 5% dextrose (“D5”), physiologically buffered saline, 0.9% saline, Hanks' solution, or Ringer's solution. Intravenous formulations may include carriers, excipients or stabilizers including, without limitation, calcium, human serum albumin, citrate, acetate, calcium chloride, carbonate, and other salts.

[0401] Intramuscular preparations, e.g. a sterile formulation of a suitable soluble salt form of the compounds of the present invention, can be dissolved and administered in a pharmaceutical excipient such as Water-for-Injection, 0.9% saline, or 5% glucose solution. Alternatively, a suitable insoluble form of the compound can be prepared and administered as a suspension in an aqueous base or a pharmaceutically acceptable oil base, such as an ester of a long chain fatty acid (e.g., ethyl oleate), fatty oils such as sesame oil, triglycerides, or liposomes.

[0402] Parenteral formulations of the compositions can contain various carriers such as vegetable oils, dimethylacetamide, dimethylformamide, ethyl lactate, ethyl carbonate, isopropyl myristate, ethanol, polyols (glycerol, propylene glycol, liquid polyethylene glycol, and the like).

[0403] Aqueous injection suspensions can also contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Non-lipid polycationic amino polymers can also be used for delivery. Optionally, the suspension can also contain suitable stabilizers or agents that increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.

[0404] Pharmaceutical compositions of the present invention can also be formulated to permit injectable, long-term, deposition. Injectable depot forms may be made by forming microencapsulated matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in microemulsions that are compatible with body tissues.

[0405] The pharmaceutical compositions of the present invention can be administered topically.

[0406] For topical use the compounds of the present invention can also be prepared in suitable forms to be applied to the skin, or mucus membranes of the nose and throat, and can take the form of lotions, creams, ointments, liquid sprays or inhalants, drops, tinctures, lozenges, or throat paints. Such topical formulations further can include chemical compounds such as dimethylsulfoxide (DMSO) to facilitate surface penetration of the active ingredient. In other transdermal formulations, typically in patch-delivered formulations, the pharmaceutically active compound is formulated with one or more skin penetrants, such as 2-N-methyl-pyrrolidone (NMP) or Azone. A topical semi-solid ointment formulation typically contains a concentration of the active ingredient from about 1 to 20%, e.g., 5 to 10%, in a carrier such as a pharmaceutical cream base.

[0407] For application to the eyes or ears, the compounds of the present invention can be presented in liquid or semi-liquid form formulated in hydrophobic or hydrophilic bases as ointments, creams, lotions, paints or powders.

[0408] For rectal administration the compounds of the present invention can be administered in the form of suppositories admixed with conventional carriers such as cocoa butter, wax or other glyceride.

[0409] Inhalation formulations can also readily be formulated. For inhalation, various powder and liquid formulations can be prepared. For aerosol preparations, a sterile formulation of the compound or salt form of the compound may be used in inhalers, such as metered dose inhalers, and nebulizers. Aerosolized forms may be especially useful for treating respiratory disorders.

[0410] Alternatively, the compounds of the present invention can be in powder form for reconstitution in the appropriate pharmaceutically acceptable carrier at the time of delivery.

[0411] The pharmaceutically active compound in the pharmaceutical compositions of the present invention can be provided as the salt of a variety of acids, including but not limited to hydrochloric, sulfuric, acetic, lactic, tartaric, malic, and succinic acid. Salts tend to be more soluble in aqueous or other protonic solvents than are the corresponding free base forms.

[0412] After pharmaceutical compositions have been prepared, they are packaged in an appropriate container and labeled for treatment of an indicated condition.

[0413] The active compound will be present in an amount effective to achieve the intended purpose. The determination of an effective dose is well within the capability of those skilled in the art.

[0414] A “therapeutically effective dose” refers to that amount of active ingredient, for example BSP polypeptide, fusion protein, or fragments thereof, antibodies specific for BSP, agonists, antagonists or inhibitors of BSP, which ameliorates the signs or symptoms of the disease or prevents progression thereof; as would be understood in the medical arts, cure, although desired, is not required.

[0415] The therapeutically effective dose of the pharmaceutical agents of the present invention can be estimated initially by in vitro tests, such as cell culture assays, followed by assay in model animals, usually mice, rats, rabbits, dogs, or pigs. The animal model can also be used to determine an initial preferred concentration range and route of administration.

[0416] For example, the ED50 (the dose therapeutically effective in 50% of the population) and LD50 (the dose lethal to 50% of the population) can be determined in one or more cell culture of animal model systems. The dose ratio of toxic to therapeutic effects is the therapeutic index, which can be expressed as LD50/ED50. Pharmaceutical compositions that exhibit large therapeutic indices are preferred.

[0417] The data obtained from cell culture assays and animal studies are used in formulating an initial dosage range for human use, and preferably provide a range of circulating concentrations that includes the ED50 with little or no toxicity. After administration, or between successive administrations, the circulating concentration of active agent varies within this range depending upon pharmacokinetic factors well-known in the art, such as the dosage form employed, sensitivity of the patient, and the route of administration.

[0418] The exact dosage will be determined by the practitioner, in light of factors specific to the subject requiring treatment. Factors that can be taken into account by the practitioner include the severity of the disease state, general health of the subject, age, weight, gender of the subject, diet, time and frequency of administration, drug combination(s), reaction sensitivities, and tolerance/response to therapy. Long-acting pharmaceutical compositions can be administered every 3 to 4 days, every week, or once every two weeks depending on half-life and clearance rate of the particular formulation.

[0419] Normal dosage amounts may vary from 0.1 to 100,000 micrograms, up to a total dose of about 1 g, depending upon the route of administration. Where the therapeutic agent is a protein or antibody of the present invention, the therapeutic protein or antibody agent typically is administered at a daily dosage of 0.01 mg to 30 mg/kg of body weight of the patient (e.g., 1 mg/kg to 5 mg/kg). The pharmaceutical formulation can be administered in multiple doses per day, if desired, to achieve the total desired daily dose.

[0420] Guidance as to particular dosages and methods of delivery is provided in the literature and generally available to practitioners in the art. Those skilled in the art will employ different formulations for nucleotides than for proteins or their inhibitors. Similarly, delivery of polynucleotides or polypeptides will be specific to particular cells, conditions, locations, etc.

[0421] Conventional methods, known to those of ordinary skill in the art of medicine, can be used to administer the pharmaceutical formulation(s) of the present invention to the patient. The pharmaceutical compositions of the present invention can be administered alone, or in combination with other therapeutic agents or interventions.

[0422] Therapeutic Methods

[0423] The present invention further provides methods of treating subjects having defects in a gene of the invention, e.g., in expression, activity, distribution, localization, and/or solubility, which can manifest as a disorder of breast function. As used herein, “treating” includes all medically-acceptable types of therapeutic intervention, including palliation and prophylaxis (prevention) of disease. The term “treating” encompasses any improvement of a disease, including minor improvements. These methods are discussed below.

[0424] Gene Therapy and Vaccines

[0425] The isolated nucleic acids of the present invention can also be used to drive in vivo expression of the polypeptides of the present invention. In vivo expression can be driven from a vector, typically a viral vector, often a vector based upon a replication incompetent retrovirus, an adenovirus, or an adeno-associated virus (AAV), for purpose of gene therapy. In vivo expression can also be driven from signals endogenous to the nucleic acid or from a vector, often a plasmid vector, such as pVAX1 (Invitrogen, Carlsbad, Calif., USA), for purpose of “naked” nucleic acid vaccination, as further described in U.S. Pat. Nos. 5,589,466; 5,679,647; 5,804,566; 5,830,877; 5,843,913; 5,880,104; 5,958,891; 5,985,847; 6,017,897; 6,110,898; and 6,204,250, the disclosures of which are incorporated herein by reference in their entireties. For cancer therapy, it is preferred that the vector also be tumor-selective. See, e.g., Doronin et al., J. Virol. 75: 3314-24 (2001).

[0426] In another embodiment of the therapeutic methods of the present invention, a therapeutically effective amount of a pharmaceutical composition comprising a nucleic acid of the present invention is administered. The nucleic acid can be delivered in a vector that drives expression of a BSP, fusion protein, or fragment thereof, or without such vector. Nucleic acid compositions that can drive expression of a BSP are administered, for example, to complement a deficiency in the native BSP, or as DNA vaccines. Expression vectors derived from virus, replication deficient retroviruses, adenovirus, adeno-associated (AAV) virus, herpes virus, or vaccinia virus can be used as can plasmids. See, e.g., Cid-Arregui, supra. In a preferred embodiment, the nucleic acid molecule encodes a BSP having the amino acid sequence of SEQ ID NO: 172 through 295, or a fragment, fusion protein, allelic variant or homolog thereof.

[0427] In still other therapeutic methods of the present invention, pharmaceutical compositions comprising host cells that express a BSP, fusions, or fragments thereof can be administered. In such cases, the cells are typically autologous, so as to circumvent xenogeneic or allotypic rejection, and are administered to complement defects in BSP production or activity. In a preferred embodiment, the nucleic acid molecules in the cells encode a BSP having the amino acid sequence of SEQ ID NO: 172 through 295, or a fragment, fusion protein, allelic variant or homolog thereof.

[0428] Antisense Administration

[0429] Antisense nucleic acid compositions, or vectors that drive expression of a BSG antisense nucleic acid, are administered to downregulate transcription and/or translation of a BSG in circumstances in which excessive production, or production of aberrant protein, is the pathophysiologic basis of disease.

[0430] Antisense compositions useful in therapy can have a sequence that is complementary to coding or to noncoding regions of a BSG. For example, oligonucleotides derived from the transcription initiation site, e.g., between positions −10 and +10 from the start site, are preferred.

[0431] Catalytic antisense compositions, such as ribozymes, that are capable of sequence-specific hybridization to BSG transcripts, are also useful in therapy. See, e.g., Phylactou, Adv. Drug Deliv. Rev. 44(2-3): 97-108 (2000); Phylactou et al., Hum. Mol. Genet. 7(10): 1649-53 (1998); Rossi, Ciba Found. Symp. 209: 195-204 (1997); and Sigurdsson et al., Trends Biotechnol. 13(8): 286-9 (1995), the disclosures of which are incorporated herein by reference in their entireties.

[0432] Other nucleic acids useful in the therapeutic methods of the present invention are those that are capable of triplex helix formation in or near the BSG genomic locus. Such triplexing oligonucleotides are able to inhibit transcription. See, e.g., Intody et al., Nucleic Acids Res. 28(21): 4283-90 (2000); McGuffie et al., Cancer Res. 60(14): 3790-9 (2000), the disclosures of which are incorporated herein by reference. Pharmaceutical compositions comprising such triplex forming oligos (TFOs) are administered in circumstances in which excessive production, or production of aberrant protein, is a pathophysiologic basis of disease.

[0433] In a preferred embodiment, the antisense molecule is derived from a nucleic acid molecule encoding a BSP, preferably a BSP comprising an amino acid sequence of SEQ ID NO: 172 through 295, or a fragment, allelic variant or homolog thereof. In a more preferred embodiment, the antisense molecule is derived from a nucleic acid molecule having a nucleotide sequence of SEQ ID NO: 1 through 171, or a part, allelic variant, substantially similar or hybridizing nucleic acid thereof.

[0434] Polypeptide Administration

[0435] In one embodiment of the therapeutic methods of the present invention, a therapeutically effective amount of a pharmaceutical composition comprising a BSP, a fusion protein, fragment, analog or derivative thereof is administered to a subject with a clinically-significant BSP defect.

[0436] Protein compositions are administered, for example, to complement a deficiency in native BSP. In other embodiments, protein compositions are administered as a vaccine to elicit a humoral and/or cellular immune response to BSP. The immune response can be used to modulate activity of BSP or, depending on the immunogen, to immunize against aberrant or aberrantly expressed forms, such as mutant or inappropriately expressed isoforms. In yet other embodiments, protein fusions having a toxic moiety are administered to ablate cells that aberrantly accumulate BSP.

[0437] In a preferred embodiment, the polypeptide is a BSP comprising an amino acid sequence of SEQ ID NO: 172 through 295, or a fusion protein, allelic variant, homolog, analog or derivative thereof. In a more preferred embodiment, the polypeptide is encoded by a nucleic acid molecule having a nucleotide sequence of SEQ ID NO: 1 through 171, or a part, allelic variant, substantially similar or hybridizing nucleic acid thereof.

[0438] Antibody, Agonist and Antagonist Administration

[0439] In another embodiment of the therapeutic methods of the present invention, a therapeutically effective amount of a pharmaceutical composition comprising an antibody (including fragment or derivative thereof) of the present invention is administered. As is well-known, antibody compositions are administered, for example, to antagonize activity of BSP, or to target therapeutic agents to sites of BSP presence and/or accumulation. In a preferred embodiment, the antibody specifically binds to a BSP comprising an amino acid sequence of SEQ ID NO: 172 through 295, or a fusion protein, allelic variant, homolog, analog or derivative thereof. In a more preferred embodiment, the antibody specifically binds to a BSP encoded by a nucleic acid molecule having a nucleotide sequence of SEQ ID NO: 1 through 171, or a part, allelic variant, substantially similar or hybridizing nucleic acid thereof.

[0440] The present invention also provides methods for identifying modulators which bind to a BSP or have a modulatory effect on the expression or activity of a BSP. Modulators which decrease the expression or activity of BSP (antagonists) are believed to be useful in treating breast cancer. Such screening assays are known to those of skill in the art and include, without limitation, cell-based assays and cell-free assays. Small molecules predicted via computer imaging to specifically bind to regions of a BSP can also be designed, synthesized and tested for use in the imaging and treatment of breast cancer. Further, libraries of molecules can be screened for potential anticancer agents by assessing the ability of the molecule to bind to the BSPs identified herein. Molecules identified in the library as being capable of binding to a BSP are key candidates for further evaluation for use in the treatment of breast cancer. In a preferred embodiment, these molecules will downregulate expression and/or activity of a BSP in cells.

[0441] In another embodiment of the therapeutic methods of the present invention, a pharmaceutical composition comprising a non-antibody antagonist of BSP is administered. Antagonists of BSP can be produced using methods generally known in the art. In particular, purified BSP can be used to screen libraries of pharmaceutical agents, often combinatorial libraries of small molecules, to identify those that specifically bind and antagonize at least one activity of a BSP.

[0442] In other embodiments a pharmaceutical composition comprising an agonist of a BSP is administered. Agonists can be identified using methods analogous to those used to identify antagonists.

[0443] In a preferred embodiment, the antagonist or agonist specifically binds to and antagonizes or agonizes, respectively, a BSP comprising an amino acid sequence of SEQ ID NO: 172 through 295, or a fusion protein, allelic variant, homolog, analog or derivative thereof. In a more preferred embodiment, the antagonist or agonist specifically binds to and antagonizes or agonizes, respectively, a BSP encoded by a nucleic acid molecule having a nucleotide sequence of SEQ ID NO: 1 through 171, or a part, allelic variant, substantially similar or hybridizing nucleic acid thereof.

[0444] Targeting Breast Tissue

[0445] The invention also provides a method in which a polypeptide of the invention, or an antibody thereto, is linked to a therapeutic agent such that it can be delivered to the breast or to specific cells in the breast. In a preferred embodiment, an anti-BSP antibody is linked to a therapeutic agent and is administered to a patient in need of such therapeutic agent. The therapeutic agent may be a toxin, if breast tissue needs to be selectively destroyed. This would be useful for targeting and killing breast cancer cells. In another embodiment, the therapeutic agent may be a growth or differentiation factor, which would be useful for promoting breast cell function.

[0446] In another embodiment, an anti-BSP antibody may be linked to an imaging agent that can be detected using, e.g., magnetic resonance imaging, CT or PET. This would be useful for determining and monitoring breast function, identifying breast cancer tumors, and identifying noncancerous breast diseases.

EXAMPLES Example 1 Gene Expression Analysis

[0447] BSGs were identified by mRNA subtraction analysis using standard methods. The sequences were extended using GeneBank sequences, Incyte's proprietary database. From the nucleotide sequences, predicted amino acid sequences were prepared. DEX0306_(—)1, DEX0306_(—)2 correspond to SEQ ID NO.1, 2 etc. DEX0157 was the parent sequence found in the mRNA subtractions. DEX0306_1 DEX0157_1 DEX0306_172 DEX0306_2 flex DEX0157_1 DEX0306_3 DEX0157_2 DEX0306_173 DEX0306_4 flex DEX0157_2 DEX0306_5 DEX0157_3 DEX0306_174 DEX0306_6 flex DEX0157_3 DEX0306_7 DEX0157_4 DEX0306_175 DEX0306_8 flex DEX0157_4 DEX0306_9 DEX0157_5 DEX0306_176 DEX0306_10 flex DEX0157_5 DEX0306_11 DEX0157_6 DEX0306_177 DEX0306_12 flex DEX0157_6 DEX0306_13 DEX0157_7 DEX0306_178 DEX0306_14 DEX0157_8 DEX0306 179 DEX0306_15 DEX0157_9 DEX0306_180 DEX0306_16 flex DEX0157_9 DEX0306_17 DEX0157_10 DEX0306_181 DEX0306_18 flex DEX0157_10 DEX0306_182 DEX0306_19 DEX0157_11 DEX0306_183 DEX0306_20 flex DEX0157_11 DEX0306_21 DEX0157_12 DEX0306_184 DEX0306_22 flex DEX0157_12 DEX0306_23 DEX0157_13 DEX0306_185 DEX0306_24 flex DEX0157_13 DEX0306_25 DEX0157_14 DEX0306_186 DEX0306_26 flex DEX0157_14 DEX0306_27 DEX0157_15 DEX0306_187 DEX0306_28 flex DEX0157_15 DEX0306_29 DEX0157_16 DEX0306_188 DEX0306_30 DEX0157_17 DEX0306_189 DEX0306_31 flex DEX0157_17 DEX0306_190 DEX0306_32 DEX0157_18 DEX0306_191 DEX0306_33 flex DEX0157_18 DEX0306_34 DEX0157_19 DEX0306_192 DEX0306_35 DEX0157_20 DEX0306_193 DEX0306_36 flex DEX0157_20 DEX0306_194 DEX0306_37 DEX0157_21 DEX0306_38 DEX0157_22 DEX0306_195 DEX0306_39 flex DEX0157_22 DEX0306_40 DEX0157_23 DEX0306_196 DEX0306_41 flex DEX0157_23 DEX0306_42 DEX0157_24 DEX0306_197 DEX0306_43 DEX0157_25 DEX0306_198 DEX0306_44 flex DEX0157_25 DEX0306_199 DEX0306_45 DEX0157_26 DEX0306_200 DEX0306_46 DEX0157_27 DEX0306_201 DEX0306_47 flex DEX0157_27 DEX0306_48 DEX0157_28 DEX0306_202 DEX0306_49 flex DEX0157_28 DEX0306_50 DEX0157_29 DEX0306_203 DEX0306_51 flex DEX0157_29 DEX0306_52 DEX0157_30 DEX0306_204 DEX0306_53 flex DEX0157_30 DEX0306_205 DEX0306_54 DEX0157_31 DEX0306_206 DEX0306_55 flex DEX0157_31 DEX0306_56 DEX0157_32 DEX0306 207 DEX0306_57 flex DEX0157_32 DEX0306_58 DEX0157_33 DEX0306_208 DEX0306_59 flex DEX0157_33 DEX0306_60 DEX0157_34 DEX0306_61 flex DEX0157_34 DEX0306_62 DEX0157_35 DEX0306_209 DEX0306_63 DEX0157_36 DEX0306_210 DEX0306_64 flex DEX0157_36 DEX0306_65 DEX0157_37 DEX0306_211 DEX0306_66 flex DEX0157_37 DEX0306_212 DEX0306_67 DEX0157_38 DEX0306_213 DEX0306_68 DEX0157_39 DEX0306_214 DEX0306_69 flex DEX0157_39 DEX0306_215 DEX0306_70 DEX0157_40 DEX0306_216 DEX0306_71 flex DEX0157_40 DEX0306_217 DEX0306_72 DEX0157_41 DEX0306_218 DEX0306_73 flex DEX0157_41 DEX0306_219 DEX0306_74 DEX0157_42 DEX0306_220 DEX0306_75 flex DEX0157_42 DEX0306_76 DEX0157_43 DEX0306_221 DEX0306_77 flex DEX0157_43 DEX0306_78 DEX0157_44 DEX0306_222 DEX0306_79 flex DEX0157_44 DEX0306_80 DEX0157_45 DEX0306_223 DEX0306_81 flex DEX0157_45 DEX0306_224 DEX0306_82 DEX0157_46 DEX0306_225 DEX0306_83 DEX0157_47 DEX0306_226 DEX0306_84 DEX0157_48 DEX0306_227 DEX0306_85 DEX0157_49 DEX0306_228 DEX0306_86 flex DEX0157_49 DEX0306_229 DEX0306_87 DEX0157_50 DEX0306_230 DEX0306_88 flex DEX0157_50 DEX0306_231 DEX0306_89 DEX0157_51 DEX0306_232 DEX0306_90 flex DEX0157_51 DEX0306_91 DEX0157_52 DEX0306_233 DEX0306_92 DEX0157_53 DEX0306_234 DEX0306_93 flex DEX0157_53 DEX0306_235 DEX0306_94 DEX0157_54 DEX0306_236 DEX0306_95 flex DEX0157_54 DEX0306_96 DEX0157_55 DEX0306_237 DEX0306_97 DEX0157_56 DEX0306_238 DEX0306_98 flex DEX0157_56 DEX0306_239 DEX0306_99 DEX0157_57 DEX0306_240 DEX0306_100 DEX0157_58 DEX0306_241 DEX0306_101 flex DEX0157_58 DEX0306_102 DEX0157_60 DEX0306_242 DEX0306_103 flex DEX0157_60 DEX0306_243 DEX0306_104 DEX0157_61 DEX0306_244 DEX0306_105 flex DEX0157_61 DEX0306_245 DEX0306_106 DEX0157_62 DEX0306_246 DEX0306_107 flex DEX0157_62 DEX0306_247 DEX0306_108 DEX0157_63 DEX0306_248 DEX0306_109 flex DEX0157_63 DEX0306_110 DEX0157_64 DEX0306_249 DEX0306_111 flex DEX0157_64 DEX0306_250 DEX0306_112 DEX0157_65 DEX0306_251 DEX0306_113 DEX0157_66 DEX0306_252 DEX0306_114 DEX0157_67 DEX0306_253 DEX0306_115 DEX0157_68 DEX0306_254 DEX0306_116 flex DEX0157_68 DEX0306_255 DEX0306_117 DEX0157_69 DEX0306_256 DEX0306_118 flex DEX0157_69 DEX0306_257 DEX0306_119 DEX0157_70 DEX0306_258 DEX0306_120 flex DEX0157_70 DEX0306_121 DEX0157_71 DEX0306_259 DEX0306_122 flex DEX0157_71 DEX0306_123 DEX0157_72 DEX0306_260 DEX0306_124 flex DEX0157_72 DEX0306_261 DEX0306_125 DEX0157_73 DEX0306_262 DEX0306_126 flex DEX0157_73 DEX0306_263 DEX0306_127 DEX0157_74 DEX0306_264 DEX0306_128 flex DEX0157_74 DEX0306_129 DEX0157_75 DEX0306_265 DEX0306_130 DEX0157_76 DEX0306_266 DEX0306_131 flex DEX0157_76 DEX0306_267 DEX0306_132 DEX0157_77 DEX0306_268 DEX0306_133 flex DEX0157_77 DEX0306_134 DEX0157_78 DEX0306_269 DEX0306_135 flex DEX0157_78 DEX0306_270 DEX0306_136 DEX0157_79 DEX0306_271 DEX0306_137 flex DEX0157_79 DEX0306_272 DEX0306_138 DEX0157_80 DEX0306_273 DEX0306_139 DEX0157_81 DEX0306_274 DEX0306_140 flex DEX0157_81 DEX0306_275 DEX0306_141 DEX0157_82 DEX0306_276 DEX0306_142 flex DEX0157_82 DEX0306_143 DEX0157_83 DEX0306_277 DEX0306_144 flex DEX0157_83 DEX0306_145 DEX0157_85 DEX0306_278 DEX0306_146 flex DEX0157_85 DEX0306_147 DEX0157_86 DEX0306_279 DEX0306_148 flex DEX0157_86 DEX0306_280 DEX0306_149 DEX0157_87 DEX0306_281 DEX0306_150 flex DEX0157_87 DEX0306_151 DEX0157_88 DEX0306_282 DEX0306_152 flex DEX0157_88 DEX0306_153 DEX0157_89 DEX0306 283 DEX0306_154 flex DEX0157_89 DEX0306_155 DEX0157_90 DEX0306_284 DEX0306_156 flex DEX0157_90 DEX0306_285 DEX0306_157 DEX0157_93 DEX0306_286 DEX0306_158 DEX0157_94 DEX0306_287 DEX0306_159 flex DEX0157_94 DEX0306_160 DEX0157_95 DEX0306_288 DEX0306_161 flex DEX0157_95 DEX0306_162 DEX0157_96 DEX0306_289 DEX0306_163 DEX0157_97 DEX0306_290 DEX0306_164 flex DEX0157_97 DEX0306_165 DEX0157_98 DEX0306_291 DEX0306_166 DEX0157_99 DEX0306_292 DEX0306_167 DEX0157_100 DEX0306_293 DEX0306_168 flex DEX0157_100 DEX0306_169 DEX0157_101 DEX0306_294 DEX0306_170 DEX0157_102 DEX0306_295 DEX0306_171 flex DEX0157_102

Example 2 Relative Quantitation of Gene Expression

[0448] Real-Time quantitative PCR with fluorescent Taqman probes is a quantitation detection system utilizing the 5′-3′ nuclease activity of Taq DNA polymerase. The method uses an internal fluorescent oligonucleotide probe (Taqman) labeled with a 5′ reporter dye and a downstream, 3′ quencher dye. During PCR, the 5′-3′ nuclease activity of Taq DNA polymerase releases the reporter, whose fluorescence can then be detected by the laser detector of the Model 7700 Sequence Detection System (PE Applied Biosystems, Foster City, Calif., USA). Amplification of an endogenous control is used to standardize the amount of sample RNA added to the reaction and normalize for Reverse Transcriptase (RT) efficiency. Either cyclophilin, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), ATPase, or 18S ribosomal RNA (rRNA) is used as this endogenous control. To calculate relative quantitation between all the samples studied, the target RNA levels for one sample were used as the basis for comparative results (calibrator). Quantitation relative to the “calibrator” can be obtained using the standard curve method or the comparative method (User Bulletin #2: ABI PRISM 7700 Sequence Detection System).

[0449] The tissue distribution and the level of the target gene are evaluated for every sample in normal and cancer tissues. Total RNA is extracted from normal tissues, cancer tissues, and from cancers and the corresponding matched adjacent tissues. Subsequently, first strand cDNA is prepared with reverse transcriptase and the polymerase chain reaction is done using primers and Taqman probes specific to each target gene. The results are analyzed using the ABI PRISM 7700 Sequence Detector. The absolute numbers are relative levels of expression of the target gene in a particular tissue compared to the calibrator tissue.

[0450] One of ordinary skill can design appropriate primers. The relative levels of expression of the BSNA versus normal tissues and other cancer tissues can then be determined. All the values are compared to a normal tissue (calibrator). These RNA samples are commercially available pools, originated by pooling samples of a particular tissue from different individuals.

[0451] The relative levels of expression of the BSNA in pairs of matching samples and 1 cancer and 1 normal/normal adjacent of tissue may also be determined. All the values are compared to a normal tissue (calibrator). A matching pair is formed by mRNA from the cancer sample for a particular tissue and mRNA from the normal adjacent sample for that same tissue from the same individual.

[0452] In the analysis of matching samples, BSNAs show a high degree of tissue specificity for the tissue of interest. These results confirm the tissue specificity results obtained with normal pooled samples.

[0453] Further, the level of mRNA expression in cancer samples and the isogenic normal adjacent tissue from the same individual are compared. This comparison provides an indication of specificity for the cancer stage (e.g. higher levels of mRNA expression in the cancer sample compared to the normal adjacent).

[0454] Altogether, the high level of tissue specificity, plus the mRNA overexpression in matching samples tested are indicative of SEQ ID NO: 1 through 171 being diagnostic markers for cancer.

Example 2B Custom Microarray Experiment

[0455] Custom oligonucleotide microarrays were provided by Agilent Technologies, Inc. (Palo Alto, Calif.). The microarrays were fabricated by Agilent using their technology for the in-situ synthesis of 60mer oligonucleotides (Hughes, et al. 2001, Nature Biotechnology 19:342-347). The 60mer microarray probes were designed by Agilent, from gene sequences provided by diaDexus, using Agilent proprietary algorithms. Whenever possible two differents 60mers were designed for each gene of interest.

[0456] All microarray experiments were two-color experiments and were performed using Agilent-recommended protocols and reagents. Briefly, each microarray was hybridized with cRNAs synthesized from polyA+ RNA, isolated from cancer and normal tissues, labeled with fluorescent dyes Cyanine3 and Cyanine5 (NEN Life Science Products, Inc., Boston, Mass.) using a linear amplification method (Agilent). In each experiment, the experimental sample was polyA+ RNA isolated from cancer tissue from a single individual and the reference sample was a pool of polyA+ RNA isolated from normal tissues of the same organ as the cancerous tissue (i.e. normal breast tissue in experiments with breast cancer samples). Hybridizations were carried out at 60° C., overnight using Agilent in-situ hybridization buffer. Following washing, arrays were scanned with a GenePix 4000B Microarray Scanner (Axon Instruments, Inc., Union City, Calif.). The resulting images were analyzed with GenePix Pro 3.0 Microarray Acquisition and Analysis Software (Axon). A total of 36 experiments comparing the expression patterns of breast cancer derived polyA+ RNA (9 stage 1 cancers, 23 stage 2 cancers, 4 stage 3 cancers) to polyA+ RNA isolated from a pool of 10 normal breast tissues were analyzed.

[0457] Data normalization and expression profiling were done with Expressionist software from GeneData Inc. (Daly City, Calif./Basel, Switzerland). Gene expression analysis was performed using only experiments that meet certain quality criteria. The quality criteria that experiments must meet are a combination of evaluations performed by the Expressionist software and evaluations performed manually using raw and normalized data. To evaluate raw data quality, detection limits (the mean signal for a replicated negative control±2 Standard Deviations (SD)) for each channel were calculated. The detection limit is a measure of non-specific hybridization. Arrays with poor detection limits were not analyzed and the experiments were repeated. To evaluate normalized data quality, positive control elements included in the array were utilized. These array features should have a mean ratio of 1 (no differential expression). If these features have a mean ratio of greater than 1.5-fold up or down, the experiments were not analyzed further and were repeated. In addition to traditional scatter plots demonstrating the distribution of signal in each experiment, the Expressionist software also has minimum thresholding criteria that employs user defined parameters to identify quality data. Only those features that meet the threshhold criteria were included in the filtering and analyses carried out by Expressionist. The thresholding settings employed require a minimum area percentage of 60% [(% pixels>background±2SD)−(% pixels saturated)], and a minimum signal to noise ratio of 2.0 in both channels. By these criteria, very low expressors and saturated features were not included in analysis.

[0458] Relative expression data was collected from Expressionist based on meeting the quality parameters described above. Sensitivity data was calculated using an analysis tool. Up- and down- regulated genes were identified using criteria for percentage of valid values obtained, and the percentage of experiments in which the gene is up- or down-regulated. These criteria were set independently for each data set, depending on the size and the nature of the data set. Results for several BSNAs are shown in the following table. The first three columns of the table contain information about the sequence itself (Oligo ID, Parent ID, and SEQ ID NO), the next 3 columns show the results obtained. ‘% valid’ indicates the percentage of 36 unique experiments total in which a valid expression value was obtained, ‘% up’ indicates the percentage of 20 experiments in which up-regulation of at least 2.5-fold was observed, and ‘% down’ indicates the percentage of the 36 experiments in which down-regulation of at least 2.5-fold was observed. The last column in Table 1 describes the location of the microarray probe (oligo) relative to the sequence. Sensitivity of up Oligo Seq and down location regulation in Oligo Seq Parent Patent # % % original location OligoID ID SEQ ID NO valid % up down seq. in FLEX seq 16052 8056 DEX0157_74, 100 11.1 33.3  75-134 1928-1987 DEX0131_52 SEQ ID NO: 127/128 24688 5998 DEX0167_22, 94.4 2.8 58.3 437-496 1093-1152 DEX0157_95, DEX0133_22, DEX0131_78 SEQ ID NO: 160/161 24689 5998 DEX0157_95, 97.2 2.8 61.1 397-456 DEX0131_78 SEQ ID NO: 160/161 27873 8713 DEX0157_74, 100 13.9 30.6 101-160 1954-2013 DEX0131_52 SEQ ID NO: 127/128 33090 5973 DEX0157_73, 97.2 2.8 44.4 408-466 2142-2200 DEX0131_56 SEQ ID NO: 125/126 33091 5973 DEX0157_73, 100 2.8 41.7 368-427 1221-1280 DEX0131_56 SEQ ID NO: 125/126

Example 3 Protein Expression

[0459] The BSNA is amplified by polymerase chain reaction (PCR) and the amplified DNA fragment encoding the BSNA is subcloned in pET-21d for expression in E. coli. In addition to the BSNA coding sequence, codons for two amino acids, Met-Ala, flanking the NH₂-terminus of the coding sequence of BSNA, and six histidines, flanking the COOH-terminus of the coding sequence of BSNA, are incorporated to serve as initiating Met/restriction site and purification tag, respectively.

[0460] An over-expressed protein band of the appropriate molecular weight may be observed on a Coomassie blue stained polyacrylamide gel. This protein band is confirmed by Western blot analysis using monoclonal antibody against 6× Histidine tag.

[0461] Large-scale purification of BSP was achieved using cell paste generated from 6-liter bacterial cultures, and purified using immobilized metal affinity chromatography (IMAC). Soluble fractions that had been separated from total cell lysate were incubated with a nickle chelating resin. The column was packed and washed with five column volumes of wash buffer. BSP was eluted stepwise with various concentration imidazole buffers.

Example 4 Protein Fusions

[0462] Briefly, the human Fc portion of the IgG molecule can be PCR amplified, using primers that span the 5′ and 3′ ends of the sequence described below. These primers also should have convenient restriction enzyme sites that will facilitate cloning into an expression vector, preferably a mammalian expression vector. For example, if pC4 (Accession No. 209646) is used, the human Fe portion can be ligated into the BamHI cloning site. Note that the 3′ BamHI site should be destroyed. Next, the vector containing the human Fe portion is re-restricted with BamHI, linearizing the vector, and a polynucleotide of the present invention, isolated by the PCR protocol described in Example 2, is ligated into this BamHI site. Note that the polynucleotide is cloned without a stop codon, otherwise a fusion protein will not be produced. If the naturally occurring signal sequence is used to produce the secreted protein, pC4 does not need a second signal peptide. Alternatively, if the naturally occurring signal sequence is not used, the vector can be modified to include a heterologous signal sequence. See, e.g., WO 96/34891.

Example 5 Production of an Antibody from a Polypeptide

[0463] In general, such procedures involve immunizing an animal (preferably a mouse) with polypeptide or, more preferably, with a secreted polypeptide-expressing cell. Such cells may be cultured in any suitable tissue culture medium; however, it is preferable to culture cells in Earle's modified Eagle's medium supplemented with 10% fetal bovine serum (inactivated at about 56° C.), and supplemented with about 10 g/l of nonessential amino acids, about 1,000 U/ml of penicillin, and about 100 μg/ml of streptomycin. The splenocytes of such mice are extracted and fused with a suitable myeloma cell line. Any suitable myeloma cell line may be employed in accordance with the present invention; however, it is preferable to employ the parent myeloma cell line (SP20), available from the ATCC. After fusion, the resulting hybridoma cells are selectively maintained in HAT medium, and then cloned by limiting dilution as described by Wands et al., Gastroenterology 80: 225-232 (1981).

[0464] The hybridoma cells obtained through such a selection are then assayed to identify clones which secrete antibodies capable of binding the polypeptide. Alternatively, additional antibodies capable of binding to the polypeptide can be produced in a two-step procedure using anti-idiotypic antibodies. Such a method makes use of the fact that antibodies are themselves antigens, and therefore, it is possible to obtain an antibody which binds to a second antibody. In accordance with this method, protein specific antibodies are used to immunize an animal, preferably a mouse. The splenocytes of such an animal are then used to produce hybridoma cells, and the hybridoma cells are screened to identify clones which produce an antibody whose ability to bind to the protein-specific antibody can be blocked by the polypeptide. Such antibodies comprise anti-idiotypic antibodies to the protein specific antibody and can be used to immunize an animal to induce formation of further protein-specific antibodies. Using the Jameson-Wolf methods the following epitopes were predicted. (Jameson and Wolf, CABIOS, 4(1), 181-186, 1988, the contents of which are incorporated by reference).

[0465] The predicted antigenicity for the amino acid sequences is as follows: SIGNAL ANTIGENICITY TRANSMEMBRANE PTM PEPTIDE Predicted Position, Position, AI Helix, Max Score, DEX ID Ave, Length Topology PTM Mean Score DEX0306_172 Myristyl 28-33; 26, .882, 53-58; 60- .574 65; Pkc_Phospho_Site 67- 69; DEX0306_173 Myristyl 13-18; Pkc_Phospho_Site 19- 21; DEX0306_174 1, i20-42o DEX0306_175 11-21, 1.07, 11 Pkc_Phospho_Site 4- 6; 12-14; DEX0306_176 52-69, 1.16, 18 Asn_Glycosylation 82- 9-18, 1.16, 10 85; Ck2_Phospho_Site 7- 10; Myristyl 79-84; Pkc_Phospho_Site 4- 6; DEX0306_177 Asn_Glycosylation 7- 10; 55-58; Ck2_Phospho_Site 22- 25; 57-60; Pkc_Phospha_Site 57- 59; Tyr_Phospho_Site 46- 52; DEX0306_178 10-47, 1.07, 38 Myristyl 33-38; 80-141, 1.03, 129-134; 62 Pkc_Phospho_Site 116- 118; 147-149; DEX0306_179 Myristyl 3-8; DEX0306_180 59-74, 1.04, 16 Ck2_Phospho_Site 4- 7; 49-52; Myristyl 45-50; 50-55; 80-85; 86-91; 95-100; Pkc_Phospho_Site 60- 62; 65-67; 69-71; DEX0306_182 Myristyl 22-27; DEX0306_184 12-36, 1.22, 25 Asn_Glycosylation 32- 35; Camp_Phospho_Site 26- 29; Ck2_Phospho_Site 9- 12; Pkc_Phospho_Site 25- 27; DEX0306_185 6-39, 1.13, 34 Asn_Glycosylation 64- 67; Ck2_Phospho_Site 37- 40; 65-68; Glycosaminoglycan 48- 51; Myristyl 14-19; 49-54; 51-56; Pkc_Phospho_Site 18- 20; 42-44; DEX0306_187 1, o25-47i Ck2_Phospho_Site 70- 73; Myristyl 7-12; Pkc_Phospho_Site 42- 44; DEX0306_188 3, i5-22o32- Myristyl 27-32; 17, .989, 54i61-83o 141-146; 144-149; .91 Pkc_Phospho_Site 17- 19; 55-57; 90-92; 111-113; DEX0306_190 Ck2_Phospho_Site 73- 76; Myristyl 12-17; 17-22; 66-71; Pkc_Phospho_Site 91- 93; DEX0306_192 Pkc_Phospho_Site 6- 8; DEX0306_193 Myristyl 4-9; DEX0306_194 415-439, Asn_Glycosylation 12- 1.14, 25 15; 19-22; 23-26; 242-251, 151-154; 513-516; 1.13, 10 873-876; 886-889; 459-528, Camp_Phospho_Site 107- 1.11, 70 110; 159-197, Ck2_Phospho_Site 72- 1.09, 39 75; 260-263; 777-810, 283-286; 319-322; 1.09, 34 463-466; 807-810; 632-669, 975-978; 1.07, 38 Glycosaminoglycan 125- 1034-1044, 128; 905-908; 1.04, 11 913-916; 1077-1103, Myristyl 13- 1.03, 27 18; 28-33; 30- 35; 52-57; 53- 58; 58-63; 61- 66; 62-67; 126- 131; 179-184; 372- 377; 529-534; 699- 704; 716-721; 717- 722; 721-726; 837- 842; 845-850; 889- 894; 906-911; 910- 915; Pkc_Phospho_Site 129- 131; 160-162; 188-190; 189-191; 356-358; 613-615; 822-824; 825-827; Prokar_Lipoprotein 44-54; DEX0306_195 Pkc_Phospho_Site 6- 8; DEX0306_196 Pkc_Phospho_Site 24- 26; 33-35; DEX0306_197 Pkc_Phospho_Site 7- 9; DEX0306_198 39-55, 1.09, 17 Ck2_Phospho_Site 92- 25-34, 1.05, 10 95; Pkc_Phospho_Site 107- 109; DEX0306_199 97-113, Ck2_Phospho_Site 150- 1.09, 17 153; 193-196; 83-92, 1.05, 10 200-203; Myristyl 11- 16; 178-183; Pkc_Phospho_Site 165- 167; Tyr_Phospho_Site 53- 61; DEX0306_200 1, i12-34o Asn_Glycosylation 20- 23; Myristyl 18-23; DEX0306_201 Myristyl 16-21; 24, .944, Pkc_Phospho_Site 24- .779 26; DEX0306_202 25-37, 1.17, 13 Ck2_Phospho_Site 12- 15; Myristyl 27-32; 31-36; 53-58; DEX0306_203 Asn_Glycosylation 28- 31; Myristyl 8-13; 62-67; 63-68; 64-69; DEX0306_204 Pkc_Phospho_Site 2- 4; DEX0306_205 Ck2_Phospho_Site 60- 63; 77-80; Myristyl 14-19; Pkc_Phospho_Site 57- 59; DEX0306_206 1, o5-24i Myristyl 4-9; DEX0306_207 Ck2_Phospho_Site 64- 67; 75-78; Myristyl 71- 76; 81-86; 85-90; DEX0306_208 Asn_Glycosylation 53- 56; 62-65; Myristyl 72-77; Pkc_Phospho_Site 63- 65; 64-66; DEX0306_209 Asn_Glycosylation 47- 50; Pkc_Phospho_Site 28- 30; 38-40; Tyr_Phospho_Site 29- 36; 30-36; DEX0306_211 Asn_Glycosylation 33- 36; Ck2_Phospho_Site 17- 20; Pkc_Phospho_Site 26- 28; DEX0306_212 30-39, 1.06, 10 Ck2_Phospho_Site 76- 17, .97, 79; Myristyl 19- .829 24; 31-36; 92-97; Pkc_Phospho_Site 12- 14; 76-78; DEX0306_213 Pkc_Phospho_Site 29- 31; DEX0306_214 Myristyl 43- 48; 48-53; DEX0306_215 104-118, Myristyl 90- 21, .973, 1.16, 15 95; 101-106; 104- .82 109; DEX0306_216 Ck2_Phospho-Site 5- 8; DEX0306_217 1, i11-33o Myristyl 42- 33, .982, 47; 54-59; 67-72; .823 Pkc_Phospho_Site 4- 6; 37-39; DEX0306_218 Asn_Glycosylation 12- 15; Ck2_Phospho_Site 8- 11; Myristyl 3-8; Pkc_Phospho_Site 23- 25; DEX0306_219 Asn_Glycosylation 21- 24; Ck2_Phospho_Site 43- 46; Pkc_Phospho_Site 23- 25; DEX0306_220 14-32, 1.13, 19 Amidation 19-22; Pkc_Phospho_Site 23- 25; DEX0306_221 Pkc_Phospho_Site 18- 20; DEX0306_223 Pkc_Phospho_Site 2- 4; DEX0306_224 Ck2_Phospho_Site 31- 34; 38-41; 57-60; 79-82; 85-88; Pkc_Phospho_Site 7- 9; DEX0306_225 1, i7-26o Asn_Glycosylation 34- 37; Ck2_Phospho_Site 36- 39; DEX0306_226 Pkc_Phospho_Site 34- 15, .918, 36; .744 DEX0306_227 52-72, 1.19, 21 1, i73-95o Amidation 66-69; Ck2_Phospho_Site 6- 9; Myristyl 74-79; 78-83; DEX0306_228 1, i20-42o DEX0306_230 1, o22-44i Prokar_Lipoprotein 23- 33; DEX0306_231 Camp_Phospho_Site 3- 6; Myristyl 31-36; 90-95; DEX0306_232 1, o15-32i Myristyl 47-52; Pkc_Phospho_Site 2- 4; DEX0306_233 Asn_Glycosylation 4- 7; DEX0306_234 24-39, 1.2, 16 Myristyl 8-13; Pkc_Phospho_Site 65- 67; DEX0306_235 560-572, Amidation 281- 1.27, 13 284; 403-406; 721- 509-519, 724; 1.23, 11 Asn_Glycosylation 633- 1126-1153, 636; 655-658; 1.19, 28 Atp_Gtp_A 507- 861-873, 514; 1.18, 13 Camp_Phospho_Site 54- 794-804, 57; 479-482; 1.16, 11 Ck2_Phospho_Site 132- 964-976, 135; 144-147; 1.16, 13 181-184; 209-212; 880-901, 217-220; 244-247; 1.16, 22 310-313; 332-335; 812-828, 345-348; 546-549; 1.11, 17 558-561; 560-563; 588-612, 593-596; 617-620; 1.09, 25 622-625; 635-638; 41-77, 651-654; 656-659; 1.07, 37 697-700; 739-742; 461-489, 740-743; 745-748; 1.07, 29 969-972; 735-751, Glycosaminoglycan 482- 1.07, 17 485; 719-722; 978-1011, Myristyl 110- 1.06, 34 115; 130-135; 142- 535-558, 147; 159-164; 230- 1.04, 24 235; 254-259; 277- 1081-1.04, 17 282; 341-346; 400- 620-644, 405; 510-515; 572- 1.03, 25 577; 582-587; 645- 654-671, 650; 721-726; 823- 1.01, 18 828; 842-847; 843- 354-382, 1, 29 848; 846-851; 872- 877; 922-927; 940- 945; 954-959; Pkc_Phospho_Site 72- 74; 83-85; 148-150; 155-157; 156-158; 209-211; 627-629; 635-637; 656-658; 660-662; 661-663; 736-738; 739-741; 745-747; 766-768; 802-804; 813-815; 913-915; 965-967; 973-975; Tyr_Phospho_Site 55- 62; 426-433; Zinc_Finger_C2h2 36- 56; 176-197; 250-270; 278-298; 337-357; 517-537; DEX0306_236 11-29, 1, 19 1, o32-54i DEX0306_237 Glycosaminoglycan 80- 83; Myristyl 14-19; 54-59; 58-63; Pkc_Phospho_Site 68- 70; 80-82; DEX0306_238 1, o62-84i Asn_Glycosylation 30- 33; Pkc_Phospho_Site 31- 33; DEX0306_239 42-63, 1.12, 22 Asn_Glycosylation 145- 148; Ck2_Phospho_Site 4- 7; 63-66; 151-154; Euk_Co2_Anhydrase 126- 142; Myristyl 25-30; 33-38; 125-130; Pkc_Phospho_Site 280- 282; DEX0306_240 20-34, 1.08, 15 Asn_Glycosylation 53- 56; Camp_Phospho_Site 41- 44; Pkc_Phospho_Site 39- 41; DEX0306_242 Myristyl 49-54; Pkc_Phospho_Site 33- 35; DEX0306_243 Ck2_Phospho_Site 23- 26; 24-27; Pkc_Phospho_Site 9- 11; 23-25; DEX0306_244 Asn_Glycosylation 4- 7; DEX0306_245 45-55, 1.15, 11 Camp_Phospho_Site 51- 54; Ck2_Phospho_Site 60- 63; Pkc_Phospho_Site 22- 24; DEX0306_246 Pkc_Phospho_Site 7- 9; 35-37; DEX0306_247 Myristyl 86-91; 22, .929, Pkc_Phospho_Site 17- .652 19; DEX0306_248 18, .993, .914 DEX0306_249 Asn_Glycosylation 2- 28, .911, 5; .74 Ck2_Phospho_Site 54- 57; Pkc_Phospho_Site 54- 56; DEX0306_250 142-180, Asn_Glycosylation 13- 1.03, 39 16; 132-135; 9-21, 1, 13 Ck2_Phospho_Site 97- 100; Pkc_Phospho_Site 17- 19; 55-57; 113-115; 134-136; 153-155; DEX0306_251 113-123, Camp_Phospho_Site 50- 1.14, 11 53; 37-60, 1.09, 24 Ck2_Phospho_Site 88- 91; Pkc_Phospho_Site 39- 41; 49-51; 88-90; Prokar_Lipoprotein 59- 69; Tyr_Phospho_Site 87- 95; DEX0306_252 Pkc_Phospho_Site 10- 12; DEX0306_253 1, i12-43o Myristyl 30-35; 30, .996, Prokar Lipoprotein 12- .862 22; DEX0306_254 Ck2_Phospho_Site 16- 19; Myristyl 31-36; 36-41; Pkc_Phospho_Site 32- 34; Rgd 25-27; DEX0306_255 Asn_Glycosylation 386- 389; 516-519; 536-539; 626-629; 638-641; 883-886; Camp_Phospho_Site 61- 64; Ck2_Phospho_Site 147- 150; 201-204; 205-208; 252-255; 394-397; 435-438; 462-465; 491-494; 511-514; 524-527; 552-555; 632-635; 646-649; 756-759; 839-842; 867-870; 887-890; Myristyl 25-30; 263-268; 751-756; 879-884; Pkc_Phospho_Site 29- 31; 107-109; 147-149; 201-203 506-508; Tyr_Phospho_Site 467- 473; DEX0306_256 65-75, 1.02, 11 Asn_Glycosylation 56- 25-50, 1.02, 26 59; Myristyl 14-19; Prokar_Lipoprotein 8-18; DEX0306_257 179-203, Amidation 267- 1.18, 25 270; 527-569, Asn_Glycosylation 176- 1.15, 43 179; 422-464, Camp_Phospho_Site 71- 1.11, 43 74; 324-327; 20-39, 1.06, 20 Ck2_Phospho_Site 42- 335-367, 45; 54-57; 75-78; 1.06, 33 99-102; 109-112; 43-117, 161-164; 197-200; 1.01, 75 206-209; 223-226; 228-231; 273-276; 283-286; 336-339; 447-450; 482-485; 497-500; 567-570; Glycosaminoglycan 246- 249; Myristyl 24- 29; 38-43; 86-91; 124-129; 249-254; 262-267; 278-283; 290-295; 332-337; 410-415; 430-435; Pkc_Phospho_Site 12- 14; 18-20; 28-30; 35-37; 54-56; 69-71; 296-298; 336-338; 411-413; 434-436; Tyr_Phospho_Site 23- 29; 137-144; 310-318; DEX0306_258 Ck2_Phospho_Site 34- 37; DEX0306_259 Asn_Glycosylation 31- 34; DEX0306_260 Camp_Phospho_Site 6- 9; Myristyl 54-59; DEX0306_261 96-105, Ck2_Phospho_Site 71- 1.19, 10 74; 101-104; Glycosaminoglycan 55- 58; Myristyl 52- 57; 54-59; 58-63; 67-72; Pkc_Phospho Site 17- 19; 137-139; 146-148; 197-199; 215-217; Prokar_Lipoprotein 164- 174; DEX0306_262 30-41, 1.02, 12 Asn_Glycosylation 86- 89; Ck2_Phospho_Site 21- 24; Myristyl 96-101; Pkc_Phospho_Site 18- 20; DEX0306_263 239-249, Amidation 72-75; 1.13, 11 Asn_Glycosylation 119- 122; 120-123; Camp_Phospho_Site 107- 110; 216-219; Ck2_Phospho_Site 28- 31; 43-46; 63-66; 160-163; 169-172; 187-190; Myristyl 69- 74; 158-163; Pkc_Phospho_Site 17- 19; 24-26; 35-37; 52-54; 59-61; 106-108; 122-124; 184-186; Prokar_Lipoprotein 248- 258; DEX0306_264 Myristyl 35-40; Pkc_Phospho_Site 21- 23; 22-24; DEX0306_265 1, i7-29o Camp_Phospho_Site 47- 50; Ck2_Phospho_Site 54- 57; Myristyl 37-42; Pkc_Phospho_Site 72- 74; DEX0306_266 Asn_Glycosylation 7- 10; 17-20; Pkc_Phospho_Site 2- 4; DEX0306_267 Amidation 43-46; Ck2_Phospho_Site 79- 82; Pkc_Phospho_Site 11- 13; 89-91; DEX0306_268 Pkc_Phospho_Site 8- 10; 45-47; Prokar_Lipoprotein 32- 42; DEX0306_269 Camp_Phospho_Site 66- 69; Ck2_Phospho_Site 12- 15; 34-37; 56-59; Myristyl 30-35; Pkc_Phospho_Site 34- 36; 56-58; DEX0306_270 49-134, 1, 86 Asn_Glycosylation 46- 49; Ck2_Phospho_Site 65- 68; 84-87; 93-96; 109-112; Myristyl 4-9; 59- 64; Pkc_Phospho_Site 60- 62; 89-91; 104-106; 115-117; 116-118; Tyr_Phospho_Site 92- 99; 117-124; 118-124; DEX0306_272 235-299, 1.1, Asn_Glycosylation 37- 65 40; 69-72; 284-287; 369-406, Ck2_Phospho_Site 85- 1.07, 38 88; 141-144; 99-109, 149-152; 192-195; 1.01, 11 204-207; Glycosaminoglycan 433- 436; Myristyl 43-48; 44-49; 96-101; 118-123; 402-407; 406-411; 432-437; 438-443; Pkc_Phospho_Site 48- 50; 433-435; Rgd 278-280; Tyr_Phospho_Site 50- 56; DEX0306_273 Pkc_Phospho_Site 6- 8; 15-17; DEX0306_(—274) Asn_Glycosylation 44- 47; DEX0306_275 Asn_Glycosylation 78- 81; Ck2_Phospho_Site 17- 20; Myristyl 13-18; DEX0306_276 Ck2_Phospho_Site 58- 61; Glycosaminoglycan 93- 96; Myristyl 28-33; 48-53; 50-55; 67-72; 71-76; Pkc_Phospho_Site 5- 7; 18-20; 44-46; 57-59; Rgd 59-61; DEX0306_277 1, o37-59i Ck2_Phospho_Site 22- 25; Myristyl 71-76; Pkc_Phospho_Site 12- 14; DEX0306_279 Myristyl 15-20; DEX0306_280 Ck2_Phospho_Site 76- 27, .985, 79; .682 Pkc_Phospho_Site 16- 18; DEX0306_281 17-29, 1.07, 13 Myristyl 5-10; 9- 14; Pkc_Phospho_Site 24- 26; DEX0306_282 1, o15-32i DEX0306_283 Asn_Glycosylation 35- 38; Ck2_Phospho_Site 37- 40; Myristyl 3-8; Pkc_Phospho_Site 57- 59; DEX0306_284 28-37, 1.09, 10 Ck2_Phospho Site 46- 21, .958, 49; .821 Pkc_Phospho_Site 32- 34; DEX0306_285 226-245, Amidation 473- 1.37, 20 476; 489-501, Asn_Glycosylation 512- 1.22, 13 515; 726-729; 1271-1284, Camp_Phospho_Site 475- 1.21, 14 478; 571-574; 1192-1203, 646-649; 1.11, 12 Ck2_Phospho_Site 29- 745-755, 32; 143-146; 1.09, 11 176-179; 228-231; 929-940, 230-233; 232-235; 1.08, 12 263-266; 294-297; 1039-1051, 388-391; 447-450; 1.08, 13 493-496; 506-509; 1133-1150, 517-520; 581-584; 1.05, 18 664-667; 890-893; 547-576, 929-932; 1.05, 30 Gram_Pos_Anchoring 670- 89-98, 1.04, 10 675; 22-53, 1.03, 32 Myristyl 49-54; 1073-1086, 56-61; 125-130; 1.03, 14 152-157; 185-190; 1243-1253, 214-219; 677-682; 1.03, 11 708-713; 840-845; 1418-1461, 921-926; 1.01, 44 Pkc_Phospho_Site 21- 23; 29-31; 143-145; 388-390; 415-417; 443-445; 530-532; 539-541; 552-554; 565-567; 581-583; 748-750; 802-804; 925-927; 931-933; 987-989; 996-998; Tyr_Phospho_Site 867- 874; Amidation 473-476; Asn_Glycosylation 512- 515; 726-729; Camp_Phospho_Site 475- 478; 571-574; 646-649; Ck2_Phospho_Site 29- 32; 143-146; 176-179; 228-231; 230-233; 232-235; 263-266; 294-297; 388-391; 447-450; 493-496; 506-509; 517-520; 581-584; 664-667; 890-893; 929-932; Gram_Pos_Anchoring 670- 675; Myristyl 49-54; 56-61; 125-130; 152-157; 185-190; 214-219; 677-682; 708-713; 840-845; 921-926; Pkc_Phospho_Site 21- 23; 29-31; 143-145; 388-390; 415-417; 443-445; 530-532; 539-541; 552-554; 565-567; 581-583; 748-750; 802-804; 925-927; 931-933; 987-989; 996-998; Tyr_Phospho_Site 867- 874; DEX0306_286 2, i13-30o35- Asn_Glycosylation 15- 54i 18; Ck2_Phospho_Site 41- 44; Myristyl 2-7; Pkc_Phospho_Site 6- 8; DEX0306_287 Asn_Glycosylation 43- 46; 51-54; Ck2_Phospho_Site 34- 37; Pkc_Phospho_Site 70- 72; DEX0306_288 Asn_Glycosylation 42- 45; Camp_Phospho_Site 12- 15; Myristyl 4-9; DEX0306_290 20-31, 1.14, 12 Pkc_Phospho_Site 6- 8; 21-23; DEX0306_291 Glycosaminoglycan 31- 34; Myristyl 30-35; DEX0306_292 Camp_Phospho_Site 8- 11; Ck2_Phospho_Site 11- 14; DEX0306_293 Ck2_Phospho_Site 36- 39; Myristyl 2-7; 94-99; DEX0306_294 31-52, 1.01, 22 Pkc_Phospho_Site 47- 49; DEX0306_295 Myristyl 56-61;

Example 6 Method of Determining Alterations in a Gene Corresponding to a Polynucleotide

[0466] RNA is isolated from individual patients or from a family of individuals that have a phenotype of interest. cDNA is then generated from these RNA samples using protocols known in the art. See, Sambrook (2001), supra. The cDNA is then used as a template for PCR, employing primers surrounding regions of interest in SEQ ID NO: 1 through 171. Suggested PCR conditions consist of 35 cycles at 95° C. for 30 seconds; 60-120 seconds at 52-58° C.; and 60-120 seconds at 70° C., using buffer solutions described in Sidransky et al., Science 252(5006): 706-9 (1991). See also Sidransky et al., Science 278(5340): 1054-9 (1997).

[0467] PCR products are then sequenced using primers labeled at their 5′ end with T4 polynucleotide kinase, employing SequiTherm Polymerase. (Epicentre Technologies). The intron-exon borders of selected exons is also determined and genomic PCR products analyzed to confirm the results. PCR products harboring suspected mutations are then cloned and sequenced to validate the results of the direct sequencing. PCR products is cloned into T-tailed vectors as described in Holton et al., Nucleic Acids Res., 19: 1156 (1991) and sequenced with T7 polymerase (United States Biochemical). Affected individuals are identified by mutations not present in unaffected individuals.

[0468] Genomic rearrangements may also be determined. Genomic clones are nick-translated with digoxigenin deoxyuridine 5′ triphosphate (Boehringer Manheim), and FISH is performed as described in Johnson et al., Methods Cell Biol. 35: 73-99 (1991). Hybridization with the labeled probe is carried out using a vast excess of human cot-1 DNA for specific hybridization to the corresponding genomic locus.

[0469] Chromosomes are counterstained with 4,6-diamino-2-phenylidole and propidium iodide, producing a combination of C-and R-bands. Aligned images for precise mapping are obtained using a triple-band filter set (Chroma Technology, Brattleboro, Vt.) in combination with a cooled charge-coupled device camera (Photometrics, Tucson, Ariz.) and variable excitation wavelength filters. Id. Image collection, analysis and chromosomal fractional length measurements are performed using the ISee Graphical Program System. (Inovision Corporation, Durham, N.C.) Chromosome alterations of the genomic region hybridized by the probe are identified as insertions, deletions, and translocations. These alterations are used as a diagnostic marker for an associated disease.

Example 7 Method of Detecting Abnormal Levels of a Polypeptide in a Biological Sample

[0470] Antibody-sandwich ELISAs are used to detect polypeptides in a sample, preferably a biological sample. Wells of a microtiter plate are coated with specific antibodies, at a final concentration of 0.2 to 10 μg/ml. The antibodies are either monoclonal or polyclonal and are produced by the method described above. The wells are blocked so that non-specific binding of the polypeptide to the well is reduced. The coated wells are then incubated for >2 hours at RT with a sample containing the polypeptide. Preferably, serial dilutions of the sample should be used to validate results. The plates are then washed three times with deionized or distilled water to remove unbound polypeptide. Next, 50 μl of specific antibody-alkaline phosphatase conjugate, at a concentration of 25-400 ng, is added and incubated for 2 hours at room temperature. The plates are again washed three times with deionized or distilled water to remove unbound conjugate. 75 μl of 4-methylumbelliferyl phosphate (MUP) or p-nitrophenyl phosphate (NPP) substrate solution are added to each well and incubated 1 hour at room temperature.

[0471] The reaction is measured by a microtiter plate reader. A standard curve is prepared, using serial dilutions of a control sample, and polypeptide concentrations are plotted on the X-axis (log scale) and fluorescence or absorbance on the Y-axis (linear scale). The concentration of the polypeptide in the sample is calculated using the standard curve.

Example 8 Formulating a Polypeptide

[0472] The secreted polypeptide composition will be formulated and dosed in a fashion consistent with good medical practice, taking into account the clinical condition of the individual patient (especially the side effects of treatment with the secreted polypeptide alone), the site of delivery, the method of administration, the scheduling of administration, and other factors known to practitioners. The “effective amount” for purposes herein is thus determined by such considerations.

[0473] As a general proposition, the total pharmaceutically effective amount of secreted polypeptide administered parenterally per dose will be in the range of about 1, μg/kg/day to 10 mg/kg/day of patient body weight, although, as noted above, this will be subject to therapeutic discretion. More preferably, this dose is at least 0.01 mg/kg/day, and most preferably for humans between about 0.01 and 1 mg/kg/day for the hormone. If given continuously, the secreted polypeptide is typically administered at a dose rate of about 1 μg/kg/hour to about 50 mg/kg/hour, either by 1-4 injections per day or by continuous subcutaneous infusions, for example, using a mini-pump. An intravenous bag solution may also be employed. The length of treatment needed to observe changes and the interval following treatment for responses to occur appears to vary depending on the desired effect.

[0474] Pharmaceutical compositions containing the secreted protein of the invention are administered orally, rectally, parenterally, intracistemally, intravaginally, intraperitoneally, topically (as by powders, ointments, gels, drops or transdermal patch), bucally, or as an oral or nasal spray. “Pharmaceutically acceptable carrier” refers to a non-toxic solid, semisolid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type. The term “parenteral” as used herein refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injection and infusion.

[0475] The secreted polypeptide is also suitably administered by sustained-release systems. Suitable examples of sustained-release compositions include semipermeable polymer matrices in the form of shaped articles, e. g., films, or microcapsules. Sustained-release matrices include polylactides (U.S. Pat. No. 3,773,919, EP 58,481), copolymers of L-glutamic acid and gamma-ethyl-L-glutamate (Sidman, U. et al., Biopolymers 22: 547-556 (1983)), poly (2-hydroxyethyl methacrylate) (R. Langer et al., J. Biomed. Mater. Res. 15: 167-277 (1981), and R. Langer, Chem. Tech. 12: 98-105 (1982)), ethylene vinyl acetate (R. Langer et al.) or poly-D-(−)-3-hydroxybutyric acid (EP 133,988). Sustained-release compositions also include liposomally entrapped polypeptides. Liposomes containing the secreted polypeptide are prepared by methods known per se: DE Epstein et al., Proc. Natl. Acad. Sci. USA 82: 3688-3692 (1985); Hwang et al., Proc. Natl. Acad. Sci. USA 77: 4030-4034 (1980); EP 52,322; EP 36,676; EP 88,046; EP 143,949; EP 142,641; Japanese Pat. Appl. 83-118008; U.S. Pat. Nos. 4,485,045 and 4,544,545; and EP 102,324. Ordinarily, the liposomes are of the small (about 200-800 Angstroms) unilamellar type in which the lipid content is greater than about 30 mol. percent cholesterol, the selected proportion being adjusted for the optimal secreted polypeptide therapy.

[0476] For parenteral administration, in one embodiment, the secreted polypeptide is formulated generally by mixing it at the desired degree of purity, in a unit dosage injectable form (solution, suspension, or emulsion), with a pharmaceutically acceptable carrier, I. e., one that is non-toxic to recipients at the dosages and concentrations employed and is compatible with other ingredients of the formulation.

[0477] For example, the formulation preferably does not include oxidizing agents and other compounds that are known to be deleterious to polypeptides. Generally, the formulations are prepared by contacting the polypeptide uniformly and intimately with liquid carriers or finely divided solid carriers or both. Then, if necessary, the product is shaped into the desired formulation. Preferably the carrier is a parenteral carrier, more preferably a solution that is isotonic with the blood of the recipient. Examples of such carrier vehicles include water, saline, Ringer's solution, and dextrose solution. Non-aqueous vehicles such as fixed oils and ethyl oleate are also useful herein, as well as liposomes.

[0478] The carrier suitably contains minor amounts of additives such as substances that enhance isotonicity and chemical stability. Such materials are non-toxic to recipients at the dosages and concentrations employed, and include buffers such as phosphate, citrate, succinate, acetic acid, and other organic acids or their salts; antioxidants such as ascorbic acid; low molecular weight (less than about ten residues) polypeptides, e. g., polyarginine or tripeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids, such as glycine, glutamic acid, aspartic acid, or arginine; monosaccharides, disaccharides, and other carbohydrates including cellulose or its derivatives, glucose, manose, or dextrins; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; counterions such as sodium; and/or nonionic surfactants such as polysorbates, poloxamers, or PEG.

[0479] The secreted polypeptide is typically formulated in such vehicles at a concentration of about 0.1 mg/ml to 100 mg/ml, preferably 1-10 mg/ml, at a pH of about 3 to 8. It will be understood that the use of certain of the foregoing excipients, carriers, or stabilizers will result in the formation of polypeptide salts.

[0480] Any polypeptide to be used for therapeutic administration can be sterile. Sterility is readily accomplished by filtration through sterile filtration membranes (e. g., 0.2 micron membranes). Therapeutic polypeptide compositions generally are placed into a container having a sterile access port, for example, an intravenous solution bag or vial having a stopper pierceable by a hypodermic injection needle.

[0481] Polypeptides ordinarily will be stored in unit or multi-dose containers, for example, sealed ampules or vials, as an aqueous solution or as a lyophilized formulation for reconstitution. As an example of a lyophilized formulation, 10-ml vials are filled with 5 ml of sterile-filtered 1% (w/v) aqueous polypeptide solution, and the resulting mixture is lyophilized. The infusion solution is prepared by reconstituting the lyophilized polypeptide using bacteriostatic Water-for-Injection.

[0482] The invention also provides a pharmaceutical pack or kit comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compositions of the invention. Associated with such container (s) can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use or sale for human administration. In addition, the polypeptides of the present invention may be employed in conjunction with other therapeutic compounds.

Example 9 Method of Treating Decreased Levels of the Polypeptide

[0483] It will be appreciated that conditions caused by a decrease in the standard or normal expression level of a secreted protein in an individual can be treated by administering the polypeptide of the present invention, preferably in the secreted form. Thus, the invention also provides a method of treatment of an individual in need of an increased level of the polypeptide comprising administering to such an individual a pharmaceutical composition comprising an amount of the polypeptide to increase the activity level of the polypeptide in such an individual.

[0484] For example, a patient with decreased levels of a polypeptide receives a daily dose 0.1-100 μg/kg of the polypeptide for six consecutive days. Preferably, the polypeptide is in the secreted form. The exact details of the dosing scheme, based on administration and formulation, are provided above.

Example 10 Method of Treating Increased Levels of the Polypeptide

[0485] Antisense technology is used to inhibit production of a polypeptide of the present invention. This technology is one example of a method of decreasing levels of a polypeptide, preferably a secreted form, due to a variety of etiologies, such as cancer.

[0486] For example, a patient diagnosed with abnormally increased levels of a polypeptide is administered intravenously antisense polynucleotides at 0.5, 1.0, 1.5, 2.0 and 3.0 mg/kg day for 21 days. This treatment is repeated after a 7-day rest period if the treatment was well tolerated. The formulation of the antisense polynucleotide is provided above.

Example 11 Method of Treatment Using Gene Therapy

[0487] One method of gene therapy transplants fibroblasts, which are capable of expressing a polypeptide, onto a patient. Generally, fibroblasts are obtained from a subject by skin biopsy. The resulting tissue is placed in tissue-culture medium and separated into small pieces. Small chunks of the tissue are placed on a wet surface of a tissue culture flask, approximately ten pieces are placed in each flask. The flask is turned upside down, closed tight and left at room temperature over night. After 24 hours at room temperature, the flask is inverted and the chunks of tissue remain fixed to the bottom of the flask and fresh media (e. g., Ham's F12 media, with 10% FBS, penicillin and streptomycin) is added. The flasks are then incubated at 37° C. for approximately one week.

[0488] At this time, fresh media is added and subsequently changed every several days. After an additional two weeks in culture, a monolayer of fibroblasts emerge. The monolayer is trypsinized and scaled into larger flasks. pMV-7 (Kirschmeier, P. T. et al., DNA, 7: 219-25 (1988)), flanked by the long terminal repeats of the Moloney murine sarcoma virus, is digested with EcoRI and HindIII and subsequently treated with calf intestinal phosphatase. The linear vector is fractionated on agarose gel and purified, using glass beads.

[0489] The cDNA encoding a polypeptide of the present invention can be amplified using PCR primers which correspond to the 5′ and 3′end sequences respectively as set forth in Example 1. Preferably, the 5′primer contains an EcoRI site and the 3′primer includes a HindIII site. Equal quantities of the Moloney murine sarcoma virus linear backbone and the amplified EcoRI and HindIII fragment are added together, in the presence of T4 DNA ligase. The resulting mixture is maintained under conditions appropriate for ligation of the two fragments. The ligation mixture is then used to transform bacteria HB 101, which are then plated onto agar containing kanamycin for the purpose of confirming that the vector has the gene of interest properly inserted.

[0490] The amphotropic pA317 or GP+aml2 packaging cells are grown in tissue culture to confluent density in Dulbecco's Modified Eagles Medium (DMEM) with 10% calf serum (CS), penicillin and streptomycin. The MSV vector containing the gene is then added to the media and the packaging cells transduced with the vector. The packaging cells now produce infectious viral particles containing the gene (the packaging cells are now referred to as producer cells).

[0491] Fresh media is added to the transduced producer cells, and subsequently, the media is harvested from a 10 cm plate of confluent producer cells. The spent media, containing the infectious viral particles, is filtered through a millipore filter to remove detached producer cells and this media is then used to infect fibroblast cells. Media is removed from a sub-confluent plate of fibroblasts and quickly replaced with the media from the producer cells. This media is removed and replaced with fresh media.

[0492] If the titer of virus is high, then virtually all fibroblasts will be infected and no selection is required. If the titer is very low, then it is necessary to use a retroviral vector that has a selectable marker, such as neo or his. Once the fibroblasts have been efficiently infected, the fibroblasts are analyzed to determine whether protein is produced.

[0493] The engineered fibroblasts are then transplanted onto the host, either alone or after having been grown to confluence on cytodex 3 microcarrier beads.

Example 12 Method of Treatment Using Gene Therapy-In Vivo

[0494] Another aspect of the present invention is using in vivo gene therapy methods to treat disorders, diseases and conditions. The gene therapy method relates to the introduction of naked nucleic acid (DNA, RNA, and antisense DNA or RNA) sequences into an animal to increase or decrease the expression of the polypeptide.

[0495] The polynucleotide of the present invention may be operatively linked to a promoter or any other genetic elements necessary for the expression of the polypeptide by the target tissue. Such gene therapy and delivery techniques and methods are known in the art, see, for example, WO 90/11092, WO 98/11779; U.S. Pat. Nos. 5,693,622; 5,705,151; 5,580,859; Tabata H. et al. (1997) Cardiovasc. Res. 35 (3): 470-479, Chao J et al. (1997) Pharmacol. Res. 35 (6): 517-522, Wolff J. A. (1997) Neuromuscul. Disord. 7 (5): 314-318, Schwartz B. et al. (1996) Gene Ther. 3 (5): 405-411, Tsurumi Y. et al. (1996) Circulation 94 (12): 3281-3290 (incorporated herein by reference).

[0496] The polynucleotide constructs may be delivered by any method that delivers injectable materials to the cells of an animal, such as, injection into the interstitial space of tissues (heart, muscle, skin, lung, liver, intestine and the like). The polynucleotide constructs can be delivered in a pharmaceutically acceptable liquid or aqueous carrier.

[0497] The term “naked” polynucleotide, DNA or RNA, refers to sequences that are free from any delivery vehicle that acts to assist, promote, or facilitate entry into the cell, including viral sequences, viral particles, liposome formulations, lipofectin or precipitating agents and the like. However, the polynucleotides of the present invention may also be delivered in liposome formulations (such as those taught in Felgner P. L. et al. (1995) Ann. NY Acad. Sci. 772: 126-139 and Abdallah B. et al. (1995) Biol. Cell 85 (1): 1-7) which can be prepared by methods well known to those skilled in the art.

[0498] The polynucleotide vector constructs used in the gene therapy method are preferably constructs that will not integrate into the host genome nor will they contain sequences that allow for replication. Any strong promoter known to those skilled in the art can be used for driving the expression of DNA. Unlike other gene therapies techniques, one major advantage of introducing naked nucleic acid sequences into target cells is the transitory nature of the polynucleotide synthesis in the cells. Studies have shown that non-replicating DNA sequences can be introduced into cells to provide production of the desired polypeptide for periods of up to six months.

[0499] The polynucleotide construct can be delivered to the interstitial space of tissues within the an animal, including of muscle, skin, brain, lung, liver, spleen, bone marrow, thymus, heart, lymph, blood, bone, cartilage, pancreas, kidney, gall bladder, stomach, intestine, testis, ovary, uterus, rectum, nervous system, eye, gland, and connective tissue. Interstitial space of the tissues comprises the intercellular fluid, mucopolysaccharide matrix among the reticular fibers of organ tissues, elastic fibers in the walls of vessels or chambers, collagen fibers of fibrous tissues, or that same matrix within connective tissue ensheathing muscle cells or in the lacunae of bone. It is similarly the space occupied by the plasma of the circulation and the lymph fluid of the lymphatic channels. Delivery to the interstitial space of muscle tissue is preferred for the reasons discussed below. They may be conveniently delivered by injection into the tissues comprising these cells. They are preferably delivered to and expressed in persistent, non-dividing cells which are differentiated, although delivery and expression may be achieved in non-differentiated or less completely differentiated cells, such as, for example, stem cells of blood or skin fibroblasts. In vivo muscle cells are particularly competent in their ability to take up and express polynucleotides.

[0500] For the naked polynucleotide injection, an effective dosage amount of DNA or RNA will be in the range of from about 0.05 μg/kg body weight to about 50 mg/kg body weight. Preferably the dosage will be from about 0.005 mg/kg to about 20 mg/kg and more preferably from about 0.05 mg/kg to about 5 mg/kg. Of course, as the artisan of ordinary skill will appreciate, this dosage will vary according to the tissue site of injection. The appropriate and effective dosage of nucleic acid sequence can readily be determined by those of ordinary skill in the art and may depend on the condition being treated and the route of administration. The preferred route of administration is by the parenteral route of injection into the interstitial space of tissues. However, other parenteral routes may also be used, such as, inhalation of an aerosol formulation particularly for delivery to lungs or bronchial tissues, throat or mucous membranes of the nose. In addition, naked polynucleotide constructs can be delivered to arteries during angioplasty by the catheter used in the procedure.

[0501] The dose response effects of injected polynucleotide in muscle in vivo is determined as follows. Suitable template DNA for production of mRNA coding for polypeptide of the present invention is prepared in accordance with a standard recombinant DNA methodology. The template DNA, which may be either circular or linear, is either used as naked DNA or complexed with liposomes. The quadriceps muscles of mice are then injected with various amounts of the template DNA.

[0502] Five to six week old female and male Balb/C mice are anesthetized by intraperitoneal injection with 0.3 ml of 2.5% Avertin. A 1.5 cm incision is made on the anterior thigh, and the quadriceps muscle is directly visualized. The template DNA is injected in 0.1 ml of carrier in a 1 cc syringe through a 27 gauge needle over one minute, approximately 0.5 cm from the distal insertion site of the muscle into the knee and about 0.2 cm deep. A suture is placed over the injection site for future localization, and the skin is closed with stainless steel clips.

[0503] After an appropriate incubation time (e. g., 7 days) muscle extracts are prepared by excising the entire quadriceps. Every fifth 15 um cross-section of the individual quadriceps muscles is histochemically stained for protein expression. A time course for protein expression may be done in a similar fashion except that quadriceps from different mice are harvested at different times. Persistence of DNA in muscle following injection may be determined by Southern blot analysis after preparing total cellular DNA and HIRT supernatants from injected and control mice.

[0504] The results of the above experimentation in mice can be use to extrapolate proper dosages and other treatment parameters in humans and other animals using naked DNA.

Example 13 Transgenic Animals

[0505] The polypeptides of the invention can also be expressed in transgenic animals. Animals of any species, including, but not limited to, mice, rats, rabbits, hamsters, guinea pigs, pigs, micro-pigs, goats, sheep, cows and non-human primates, e. g., baboons, monkeys, and chimpanzees may be used to generate transgenic animals. In a specific embodiment, techniques described herein or otherwise known in the art, are used to express polypeptides of the invention in humans, as part of a gene therapy protocol.

[0506] Any technique known in the art may be used to introduce the transgene (i. e., polynucleotides of the invention) into animals to produce the founder lines of transgenic animals. Such techniques include, but are not limited to, pronuclear microinjection (Paterson et al., Appl. Microbiol. Biotechnol. 40: 691-698 (1994); Carver et al., Biotechnology (NY) 11: 1263-1270 (1993); Wright et al., Biotechnology (NY) 9: 830-834 (1991); and Hoppe et al., U.S. Pat. No. 4,873,191 (1989)); retrovirus mediated gene transfer into germ lines (Van der Putten et al., Proc. Natl. Acad. Sci., USA 82: 6148-6152 (1985)), blastocysts or embryos; gene targeting in embryonic stem cells (Thompson et al., Cell 56: 313-321 (1989)); electroporation of cells or embryos (Lo, 1983, Mol Cell. Biol. 3: 1803-1814 (1983)); introduction of the polynucleotides of the invention using a gene gun (see, e. g., Ulmer et al., Science 259: 1745 (1993); introducing nucleic acid constructs into embryonic pleuripotent stem cells and transferring the stem cells back into the blastocyst; and sperm mediated gene transfer (Lavitrano et al., Cell 57: 717-723 (1989); etc. For a review of such techniques, see Gordon, “Transgenic Animals,” Intl. Rev. Cytol. 115: 171-229 (1989), which is incorporated by reference herein in its entirety.

[0507] Any technique known in the art may be used to produce transgenic clones containing polynucleotides of the invention, for example, nuclear transfer into enucleated oocytes of nuclei from cultured embryonic, fetal, or adult cells induced to quiescence (Campell et al., Nature 380: 64-66 (1996); Wilmut et al., Nature 385: 810813 (1997)).

[0508] The present invention provides for transgenic animals that carry the transgene in all their cells, as well as animals which carry the transgene in some, but not all their cells, I. e., mosaic animals or chimeric. The transgene may be integrated as a single transgene or as multiple copies such as in concatamers, e.g., head-to-head tandems or head-to-tail tandems. The transgene may also be selectively introduced into and activated in a particular cell type by following, for example, the teaching of Lasko et al. (Lasko et al., Proc. Natl. Acad. Sci. USA 89: 6232-6236 (1992)). The regulatory sequences required for such a cell-type specific activation will depend upon the particular cell type of interest, and will be apparent to those of skill in the art. When it is desired that the polynucleotide transgene be integrated into the chromosomal site of the endogenous gene, gene targeting is preferred. Briefly, when such a technique is to be utilized, vectors containing some nucleotide sequences homologous to the endogenous gene are designed for the purpose of integrating, via homologous recombination with chromosomal sequences, into and disrupting the function of the nucleotide sequence of the endogenous gene. The transgene may also be selectively introduced into a particular cell type, thus inactivating the endogenous gene in only that cell type, by following, for example, the teaching of Gu et al. (Gu et al., Science 265: 103-106 (1994)). The regulatory sequences required for such a cell-type specific inactivation will depend upon the particular cell type of interest, and will be apparent to those of skill in the art.

[0509] Once transgenic animals have been generated, the expression of the recombinant gene may be assayed utilizing standard techniques. Initial screening may be accomplished by Southern blot analysis or PCR techniques to analyze animal tissues to verify that integration of the transgene has taken place. The level of mRNA expression of the transgene in the tissues of the transgenic animals may also be assessed using techniques which include, but are not limited to, Northern blot analysis of tissue samples obtained from the animal, in situ hybridization analysis, and reverse transcriptase-PCR (rt-PCR). Samples of transgenic gene-expressing tissue may also be evaluated immunocytochemically or immunohistochemically using antibodies specific for the transgene product.

[0510] Once the founder animals are produced, they may be bred, inbred, outbred, or crossbred to produce colonies of the particular animal. Examples of such breeding strategies include, but are not limited to: outbreeding of founder animals with more than one integration site in order to establish separate lines; inbreeding of separate lines in order to produce compound transgenics that express the transgene at higher levels because of the effects of additive expression of each transgene; crossing of heterozygous transgenic animals to produce animals homozygous for a given integration site in order to both augment expression and eliminate the need for screening of animals by DNA analysis; crossing of separate homozygous lines to produce compound heterozygous or homozygous lines; and breeding to place the transgene on a distinct background that is appropriate for an experimental model of interest.

[0511] Transgenic animals of the invention have uses which include, but are not limited to, animal model systems useful in elaborating the biological function of polypeptides of the present invention, studying conditions and/or disorders associated with aberrant expression, and in screening for compounds effective in ameliorating such conditions and/or disorders.

Example 14 Knock-Out Animals

[0512] Endogenous gene expression can also be reduced by inactivating or “knocking out” the gene and/or its promoter using targeted homologous recombination. (E. g., see Smithies et al., Nature 317: 230-234 (1985); Thomas & Capecchi, Cell 51: 503512 (1987); Thompson et al., Cell 5: 313-321 (1989); each of which is incorporated by reference herein in its entirety). For example, a mutant, non-functional polynucleotide of the invention (or a completely unrelated DNA sequence) flanked by DNA homologous to the endogenous polynucleotide sequence (either the coding regions or regulatory regions of the gene) can be used, with or without a selectable marker and/or a negative selectable marker, to transfect cells that express polypeptides of the invention in vivo. In another embodiment, techniques known in the art are used to generate knockouts in cells that contain, but do not express the gene of interest. Insertion of the DNA construct, via targeted homologous recombination, results in inactivation of the targeted gene. Such approaches are particularly suited in research and agricultural fields where modifications to embryonic stem cells can be used to generate animal offspring with an inactive targeted gene (e. g., see Thomas & Capecchi 1987 and Thompson 1989, supra). However this approach can be routinely adapted for use in humans provided the recombinant DNA constructs are directly administered or targeted to the required site in vivo using appropriate viral vectors that will be apparent to those of skill in the art.

[0513] In further embodiments of the invention, cells that are genetically engineered to express the polypeptides of the invention, or alternatively, that are genetically engineered not to express the polypeptides of the invention (e. g., knockouts) are administered to a patient in vivo. Such cells may be obtained from the patient (I. e., animal, including human) or an MHC compatible donor and can include, but are not limited to fibroblasts, bone marrow cells, blood cells (e. g., lymphocytes), adipocytes, muscle cells, endothelial cells etc. The cells are genetically engineered in vitro using recombinant DNA techniques to introduce the coding sequence of polypeptides of the invention into the cells, or alternatively, to disrupt the coding sequence and/or endogenous regulatory sequence associated with the polypeptides of the invention, e. g., by transduction (using viral vectors, and preferably vectors that integrate the transgene into the cell genome) or transfection procedures, including, but not limited to, the use of plasmids, cosmids, YACs, naked DNA, electroporation, liposomes, etc.

[0514] The coding sequence of the polypeptides of the invention can be placed under the control of a strong constitutive or inducible promoter or promoter/enhancer to achieve expression, and preferably secretion, of the polypeptides of the invention. The engineered cells which express and preferably secrete the polypeptides of the invention can be introduced into the patient systemically, e. g., in the circulation, or intraperitoneally.

[0515] Alternatively, the cells can be incorporated into a matrix and implanted in the body, e. g., genetically engineered fibroblasts can be implanted as part of a skin graft; genetically engineered endothelial cells can be implanted as part of a lymphatic or vascular graft. (See, for example, Anderson et al. U.S. Pat. No. 5,399,349; and Mulligan & Wilson, U.S. Pat. No. 5,460,959 each of which is incorporated by reference herein in its entirety).

[0516] When the cells to be administered are non-autologous or non-MHC compatible cells, they can be administered using well known techniques which prevent the development of a host immune response against the introduced cells. For example, the cells may be introduced in an encapsulated form which, while allowing for an exchange of components with the immediate extracellular environment, does not allow the introduced cells to be recognized by the host immune system.

[0517] Transgenic and “knock-out” animals of the invention have uses which include, but are not limited to, animal model systems useful in elaborating the biological function of polypeptides of the present invention, studying conditions and/or disorders associated with aberrant expression, and in screening for compounds effective in ameliorating such conditions and/or disorders.

[0518] All patents, patent publications, and other published references mentioned herein are hereby incorporated by reference in their entireties as if each had been individually and specifically incorporated by reference herein. While preferred illustrative embodiments of the present invention are described, one skilled in the art will appreciate that the present invention can be practiced by other than the described embodiments, which are presented for purposes of illustration only and not by way of limitation. The present invention is limited only by the claims that follow.

1 295 1 591 DNA Homo sapien 1 gctcttcctg tctacaaagg ggactgctca cagtggcctc agcttggtgg ttttgagggg 60 ccgccccccg gccctccata agggtatcct gggcctgaga attctgcatc tgccattgga 120 tggatgtaca gcctcaaatg gaagtgagtc ccacgggaga tgggtccgag gtccaggctg 180 tggccatcca gccccctgtg gcttgtccag cctctgtgca cccctggtgt cttcactcca 240 ggggcagaca gtagccactg cagttccttt cttcgtgaga taacagtagt gatagcagct 300 ggggctaaca ggctaggctt agtgtcctgc gcatttggtc agcttctcac tcgatcctcc 360 ctaaagcaat ggggaggccc ccactagccc agttttcagg aagtcaactg ggaggttaga 420 tgggggccag aggtcccaca gctactgatg gcccgagcca ggttgagctt tcctggatgt 480 ccagtccgga tcccacttgc agatctcatg ctctcagata ggtgggacaa gttcttttgt 540 cacagtgctg gctctgtcct gaggcctcat tgctggctgg tgtgctctgc t 591 2 2754 DNA Homo sapien 2 gccagaagca gcctcagctt ggcaaggtgt ggagatgact gctgttccct tcgcatttgg 60 ggaaaacagg ctccctcggt agctcgatga tcctcttttg atcttgtgtg acctcctgga 120 gagtggatga cgctggtggc cttagctttt ctagacagtg taaattgcac tgggcgatgt 180 ccccagagca gggcaaggtc tctagagcgg gtctcccaca tgactggctt cacacaggca 240 cttccgctcg ggttgcatgc tctgtgtcat cttaccggtc cagggttgca ggtaggaaat 300 gtttgtaccc tcttctgatt gccacctcct tcccatcgcc ccttagggac agggcttgag 360 ggccagtgag gcgctggtca ggcaccccag gcctccttgg gacctgccca ggggcaccct 420 gagagctcct gaaaccccca cttagcttcc agacctttct gcaaaagctc ctcctggctt 480 tcctccctcc cccaatctat gggtcacagc taacagatct gagggcaact gctgtgctag 540 tggccagggc tgcacctgcc atccccggct ctgccacttt agggccttct agaggcagtg 600 tccttaggaa gtagctctga ggcatgggtt ttctgctcct gtgcagggca gctgatggga 660 taaggtgggg aaggacggtc agtgcttggg ccccagctgg ccagcctggc gatggggaaa 720 ccaaaccatg tcccccagcg aagggccaga gtgggaacct gtcctcatgc ccttcgtcct 780 gaggagccct gaggtgggca gcaggggcca ggggaagttt tcaggccttc atcaaagaga 840 acaacatcct cagctccgca cccctcatcc tgtatcagca cttaccggtg tgtgactgcc 900 cttgtcagct agcatacggt gggcccacct ggcccactgg ctgtttatgc cactgattta 960 tgatagggaa tattatcttt gaacccaatg aagtgttttc tcccccatca caaaaaaaaa 1020 aattcttatt tttagtagac atgtatttac caaaaatatg tactcaatta ttgtattttg 1080 gattttatca atttaaaaat tgtggaaatt tgtttgctct tacgccaaca taatattgat 1140 tttgcctctt ggctctgaaa gcccaaaata tttaccgtct agcccgttac agaaaaagtc 1200 tgctgactac tgagccagac ctccattacc tccatccctg ttggattatt taaagaaagc 1260 ctcagacagt aagggctttt ttaaaagaat aaaatgactt ggtttgcgct tggaagcagg 1320 ggaagcattc agatgagcgg tttctgcatt aaccctgcct atcacgcatc tcgtgtcctg 1380 tgtggctggc gagcccccct tggaaggttc tggtgcttca gctggctcct gcagagtcca 1440 ccccgcctcg tggtgggaat gcagagccct ttgctttcct tcttgccgcc tgcttcctgt 1500 tcctggggac ccgctgggcc tttggtctgc atcccctggc caggtccctc agggttgatg 1560 cgtggagaag gactttgagc agtggtgggc agcagtggcc tcctggccag ctcacactct 1620 tgtcctggga ggggcagcct gatctcacct ccacctagta ccttggggac tgaggacctt 1680 ttggcttctc tggagcctgc aagcctcttc ccatgtgtcc agctgctctt cctgctacaa 1740 aggggactgc tcacagtggc ctcagcttgg tggttttgag gggccgcccc ccggccctcc 1800 ataagggtat cctgggcctg agaattctgc atctgccatt ggaggatgga cagcctcaaa 1860 tggaaggagt cccacgggag atgggtccga ggtccggctg tggccatcca gccccctgtg 1920 gcttgtccag cctctgtgca cccctggtgt cttcactcca ggggcagaca gcagccactg 1980 cagttccttt cttcgtgagt aacagtagtg atagcagctg gggctaacag gctaggcttt 2040 gtgttctgcg catttggtca gcttctcact cgatcctccc taaagcaatg gggaggcccc 2100 cactagccca gttttcagga agtcaactgg gaggttagat gggggccagg gtcccacagc 2160 tactgatggc ccgagccagg ttgagcttcc tggtgtccag tccggatccc acttgcagat 2220 ctcatgctct cagataggtg ggacaagttc ttttgtcaca gtgctggctc tgtcctgagg 2280 cctcattgct ggctgggtgt gctctgctgg gaaaagcttt gcggggcttg cttggttaac 2340 cacagaagag aaggggactg tttggggtgc ctctctgcag cctccccgtg ctgggtggaa 2400 gcacggttac tgtgttctct aatgttcatg tatttaaaat gatttctttc taaagatgta 2460 acctccacac ctttctccag attgggtgac tcttttctaa aggtggtggg agtatctgtc 2520 ggggtggtgt ggcccttgga tgggtcaggt gggtgtgaga ggtcctgggg aggtgggcgt 2580 tgagctcaaa gttgtcctac tgccatgttt ttgtacctga aataaagcat attttgcact 2640 tgttactgta ccatagtgcg gacgagaagt ctgtatgtgg gatctgtgct tgggttagaa 2700 tgcaaataaa actcacattt gtaagaaaaa aaaaaaaaat aaaaagatgc ggcc 2754 3 856 DNA Homo sapien 3 acgttaaaat taagaactta ggctttggtt taaaaaacaa taaatgaagt gaaaaaaaca 60 agccacagag taaaagaaga tacttgcagc aagtgataaa ggattagtat ccaggatata 120 taaagactgt tattgagtca atgtgaaagg gagaaaaaca cctgaagcaa agaatggatg 180 ccggcattaa ataggcactt caaagaggaa ccatgaacga ccaaaatcaa gtgagtaggt 240 gaccagttcc cattagtaat taggaaatag caaattaaga ccacaaagag ggcagtgagg 300 gtggctcaca cacctctaat ctcagcggct tgggagtcca ggcccagagg atcccttgag 360 gccaggaggt ggagtctagc ctgggaaaca tagcaagacc ctgtctctac aaaaaaataa 420 ataaataaaa taagaaaaaa gtaaaccaca aggagatgac ttaccaccag gcaaaaatat 480 taaagtatgc taataccaag tatcaagaag aatgaagcaa gatagctcaa atatgctttt 540 gaaggaaata tactgggctt ccattcattc tgaaataccc cttatttaag atactctatt 600 atattaaata cagttccaaa acaaaagaaa tccaaagaac aaaaaactaa cccaatactt 660 ttatcacttg taattgtata ttacaccata ttgaaagata tattttacga cttattagag 720 aacgattttt aaattggata tcactctgtg catacaaata aaataaagtg attaaggttc 780 taacaaaaaa acaaaccaca acaccaaagg ctttttaagg gggggaggaa taaggaaagg 840 ggcccaaaaa agggac 856 4 1580 DNA Homo sapien 4 gtcccttttt tgggcccctt tccttattcc tccccccctt aaaaagcctt tggtgttgtg 60 gtttgttttt ttgttagaac cttaatcact ttattttatt ttgtatgcac aagagtgata 120 tccaattaaa aatcgttctc taataagtct aaaatatatc tttcaatatg tgtaatatac 180 aaattacaag tgataaaagt attgggttag ttttttgttc tttgatttct tttgttttgg 240 aactgtattt aatataatag agtatcttaa ataaggggta tttcagaatg aatgaagccc 300 agtatatttc cttcaaaagc atatttgagc tatcttgctt cattcttctt gatacttggt 360 attagcatac tttaatattt ttgcctggtg gtaagtcatc tccttgtggt ttactttttt 420 cttattttat ttatttattt ttttgtagag acagggtctt gctatgtttc ccaggctaga 480 ctccacctcc tggcctcaag ggatcctctg ggcctggact cccaagccgc tgagattaga 540 ggtgtgtgag ccaccctcac tgccctcttt gtggtcttaa tttgctattt cctaattact 600 aatgggaact ggtcacctac tcacttgatt ttggtcgttc atggttcctc tttgaagtgc 660 ctatttaatg ccggcatcca ttctttgctt caggtgtttt tctccctttc acattgactc 720 aataacagtc tttatatatc ctggatacta atcctttatc acttgctgca agtatcttct 780 tttactctgt ggcttgtttt tttcacttca tttattgttt tttaaaccaa agcctaagtt 840 cttaatttta acgtacttga actgacattt tctaccctgg ccccctccca cccttagttc 900 ccagacacct cttatgatct ggggtcgagg agcccgcctt cctggcggtc tcagctgggg 960 cctggggagc gaaggcggcg ggcgctcgcg ggaggagctg cgcgattcgg atgctgggga 1020 ggtgaagctc gcggggccgc caggccgccg gggtaaggaa ggccgggagg ccgcgggggt 1080 ccacggcgcg gagggagccg caggcaccgg gcacagccct cgcccatcgc cgagacccgg 1140 caggcccagg agccagaggg cggcggcgtg agagggaacc gcctccaaag gacgccctcg 1200 ccctcccgca ggcatagtcg caggcgccag tcccggtccg agccagctgg gggtggctcc 1260 ggggagctga gccgggggag ggccgggccg cccaacggat caataggggg gtttctccca 1320 ggttgccgtt tctctggccc gcgacgccct acccgccgga gccgcccaac cgcaagcccc 1380 gccccgaagg cgggtgcagc caggaaggcg gggcctggtg gcctctgggc gctggcgcca 1440 agttcagagc cgcgccctgg gctgggcggt ggcggccgcg tctgcacttc cccccctgcg 1500 cgcctctgga gagcccggga gagacgcacc ctcaggtcgg ccaagaccga gaacaagcgg 1560 gcgcgggcag cggagcccat 1580 5 800 DNA Homo sapien 5 tggtcgcggc cgaggtacaa aggctttgag gtccatggac tatacttgtc ccatttatca 60 tcccaggtgg tgctttgacc ctagggatac cctggctatt aagataaaaa gatttgtgga 120 cattaaaatt atgaatatgt cagtaataat ccagcacaca ttgaaatatt gacacagatt 180 accataattt gtgcaacatc ttataaacaa tgtcatttcc acagtagtct aaggcttcac 240 cagcctggcc cactgtatct agactttagg ttcattttaa ttaattatgc tttccttctc 300 tgtatcattt gggaagttga taaatatcac ttccttagat accttcattc agtgatatat 360 ctggctttta caattaaatt ggaaaaggta agtttctctt tggtgggttg agagttggac 420 catcaattct aatctacaaa aggaaattca tgatttcact ctgacgccta ggatctagcc 480 aaggctggtc tgcagtatca gatgtccaaa ctcatctact attagccata ttttgtgagt 540 cgtttgtcta aactttgtca aaaatgcctt tgccatgatt ttgttgctat ctggatttca 600 aacatggaca gttaggaaga tgtgcattga agtaggaaaa ttttgttcag catctgctgt 660 tatttatttt ttaccacttc aaaaatggcc actgtctttt taacaaacac caacgacaac 720 aacacacaaa acaaaaaaaa acaccctgcg gcttaccctg gccctccttt tccctgttga 780 attgtttccc ccccaatcac 800 6 956 DNA Homo sapien 6 atttataagg cccttcaaat ttgtggcttc ctttctcata cttctcaagt ataatgaaag 60 ggggagaaaa accccaccat caacacaaaa gaaggctata aagactgtgc accttttaac 120 aagtcaattt gtagtcagtc cctgggcctg tctttttttt tttttaattt tgaagctacc 180 tgaggtttag aattccttca gccctagctg cttttattct gctttttatt taaacaaaaa 240 gagggggagg atctgaagga aactagtttt ctgtacaaag gctttgaggt ccatggacta 300 tacttgtccc atttatcatc ccaggtggtg ctttgaccct gccataccct ggctattaag 360 ataaaaagat ttgtggacat taaaattatg aatatgtcag taataatcca gcacacattg 420 aaatattgac acagattacc ataatttgtg caacatctta taaacaatgt catttccata 480 gtagtctaag gcttcaccag cctggcccac tgtatctaga ctttaggttc attttaataa 540 ttatgctttc cttctctgta tcatttggga agttgataaa tatcacttcc ttagatacct 600 tcattcagtg atatatctgg cttttacaat taaattggaa aaggtaagtt tctctttggt 660 gggttgagag ttggaccatc aattctaatc tacaaaagga aattcatgat ttcactctga 720 cgcctaggat ctagccaagg ctggtctgca gtatcagatg tccaaactca tctactatta 780 gccatatttt gtgagtcgtt tgtctaaact ttgtcaaaaa tgcctttgcc atgattttgt 840 tgctatctgg atttcaaaca tggacagtta ggaagatgtg cattgaagta ggaaaatttt 900 gttcagattt gctgttattt attttttaaa ttaaaaatgg aaatgtaaaa aaaaaa 956 7 489 DNA Homo sapien 7 actatgtgtt aacataatcc caccttctta gagctttgtt ccttctgaag gtgtatagat 60 acagcttgtc ttgaaatgtc tttctccaca taatgaagca tgctgaatgc tgggaatctg 120 gagcagcagc cctgggagcc ctgagttttg aagtgttttg gtttgcttca aaggttagaa 180 gaacttgata tgtatggcaa acaactttag aatactagtt actcactaac atgaggcggg 240 taatgttgct ctagattcta tattccagta aagccagctt ttcttattat tggagtaggc 300 aaatgaatgg cattagaatt agtgggtggc ttgtaagttg tagttatagg cactttacca 360 cttcctgcca ttagcaggca tccttgtttt ttcttctttt ccctctttgt tccttctttt 420 ccctttctcc ttatacattt tctttctcta ctttaattct ccttcctcct tactgtagat 480 cccaagctt 489 8 3190 DNA Homo sapien 8 ctctcattag cctgttcaga gtcttggggg aaattgagat ttttgagatt ttttttaaaa 60 actcaaatat tttactagtt tgcctgccat tttatttctt ttacaaagca gaagcatata 120 ccaatttatc acagtatttt agtaaatact gcaacattca tccttaaatg ttcaccaaga 180 aaagcatctt tgtagtagtg ctggaaaact attcagaata tacagataaa aatgctgttc 240 tttaattgct tacattgctt cttcccataa aaagcaaaaa ggaatcagtg cttgctattg 300 ctcctttcct tgaagttgta acaattgata catatattat gagttgactg gtcgattctg 360 tacctggccc atcctttaga atgttcttgt catgtagcag tcctacgtac tcttttcatg 420 agcagtctgt gatctcactc tgtgagttca gctattactc gctcgtggga gcttaatctt 480 ttcaaaatga agttgattta aaaagtcttc aggcagagta atcatgttag aggtggtatt 540 cgatggaaga aagtttagag agttaggagt gggggtagaa ttctagaatt tataagagtc 600 caggaagcat agcagtcagg ggcaaaaatt agcgtaatat ggagtaggca atagaggagc 660 tactggagtc agaagtcact gcagagtgca acataggaag atggactcct agcttacatg 720 agattccctg cagctgtaat atagacaatt cccacatggc tgttctacac agaattacct 780 gctaagattt tttgtttatt tttgtttgag tggtattttc actccaattg tataatggaa 840 atcagtggga aaatagggtt taccttatat tcatgagttc tagtttctac tgttctgcta 900 tgtgtttcta agcaagagca aaggatactt catacttttt tcgttatatg attgatcttc 960 aaattgggat ttaccttttt caatatgttt taaagtagtc ttattcctct tttgatttgt 1020 taaacaagca ttttagttca gctattgaat agccttccaa aaaattaatt cagccttgca 1080 ggtaagtacc atactaagac tttaacccaa tagtttttaa tcattctgcc tttattccaa 1140 actgtaaatc tgtacacata agataaaaca tactaagtat tgcataaatt gttaacgtta 1200 cagtaaattg ttatctgcag ggctgacaga cataatgttg gtgggcaact gtgatcctat 1260 acatacatat atgcaaaagg ggattttaaa agtgcagatt atagagtaga ttgacaaatt 1320 ttattttata ttcagttgtc ctctctgctt ccatctgtgt tgctctctta gttgagagag 1380 agttagccat ttgacgattt taagtcagtg ggaacttatt tttagttact caataaaatt 1440 aatattttat ttgtatttta acttacagag taggttggta ataacagctg aactgtgtaa 1500 cattgttgct tcaaattgaa gtttatatta tgaacattca gaatcaatgc tcatgtagca 1560 gcatattatt gagctatttt gagtttgaaa tgtggagaaa cgctaaacca tgtactatgt 1620 gttaacataa tcccaccttc ttagagcttt gttccttctg aaggtgtata gatacagctt 1680 gtcttgaaat gtctttctcc acataatgaa gcatgctgaa tgctgggaat ctggagcagc 1740 agccctggga gccctgagtt ttgaagtgtt ttggtttgct tcaaaggtta gaagaacttg 1800 atatgtatgg caaacaactt tagaatacta gttactcact aacatgaggc gggtaatgtt 1860 gctctagatt ctatattcca gtaaagccag cttttcttat tattggagta ggcaaatgaa 1920 tggcattaga attagtgggt ggcttgtaag ttgtagttat aggcacttta ccacttcctg 1980 ccattagcag gcatccttgt tttttcttct tttccctctt tgttccttct tttccctttc 2040 tccttataca ttttctttct ctactttaat tctccttcct ccttactgta gatcccaagc 2100 ttctagctta ggtttgcaag tcatattgct tggccctcca cattcactga gaggtgaaga 2160 taggctgacc ccctgtcctc ttacatttga gggatcatag actgctgtgt gaattctgga 2220 aagtctcagg tccctaccag ggcactgaat ggcttctcaa tggctgtaga gacagtacag 2280 ttttccaaag cagcctaatt catctggaca gctaccaggc actttggaaa gttggttcag 2340 ttactactat gaggccataa tatatttgct ggtattaaaa ttcttcagaa ttggaattac 2400 tatttgaaat aatattttgg ttgacttaag ttttgagaga caattctaaa attgatctag 2460 agactcattc aatagcaatg tgacctttta aatacttaca ttaagtaaaa ctgccagtag 2520 attaaatcat atatatatat atatatatat atatatatgt aagagcttcc tctatttact 2580 actgttgaac ttcagtaatt tttagaggct aaataatggt cagaatgttt ttaagtgtgc 2640 tcttttatta catgcttgtg caggttttgt aattcagtac agaaaagttt aaccttgtac 2700 atttttgtat gtaaaaagtc ttttaagtag tcttatcctt atttaaataa acagaataaa 2760 attaccttga gtaggtctgt tattcttatt aaaatggaaa aatgctctgt aatgacttga 2820 tctgttttta tttgagtgaa caattttgga aagtattctt tatagtacaa ctttctatac 2880 ctggattgat taagatcaga tgtgattcga gtagtccagc catatcttgt agcccttctt 2940 tgaatgagag ggtggctgga gtggtctggt gctgggatat cacggtgcta cagagcctga 3000 catgttgact gtcactacat gttgagggat ggaaatagaa gtctctgaac ttcccatgta 3060 atattaaagc tcttaacaaa atgagacaaa ctagagattc agttgagaga ttttatgtta 3120 gagtgatctg aaaaaaagtt aatttctaaa ctgctatctt aatattatta tatttggaga 3180 ctgatgctgt 3190 9 672 DNA Homo sapien 9 ggtcgcggcc gaggtactat tgctctggct cctggccctc tccttgctat gggtcttacc 60 ctcaagtcgc tctgtgattc aaagatgaac tgccaatcaa atgttcctct aatgaaagat 120 ccaatcactc tacagcatgt gtgtattcaa agaacctatc taagactttc ttttggtcat 180 ggtgggaggc tgttgctgaa aacataccag agcccattgt ggaggtcagc tgacaggccg 240 catgaccttg gcaatggact actggtcatc tgggactgct taggactgtg caatggaact 300 tgggggcaaa actgatggag acagccaatg ggccttaaat ccagcaggca aagacagagt 360 aagttcttat ttgtgtagcc cagggcttat caaagtgtgg ttcttggacc acgtgcatca 420 gtatcagctg taagtatttg gcaaaatgca gattcccggg ccctgcacca aacagattga 480 ctttgaatct ctgggggttg ggctaaaaaa aaagaaaaaa aaaccctaca ttttaaacaa 540 gctcttcaga tgacccttgt gtaagtttga gagcatctgc tggaaaacca ctagaatttg 600 caaacggcac tcaaaatact ccagccagtc cactagccaa agaccagatc tgagaccgga 660 tgggaaatta tc 672 10 997 DNA Homo sapien 10 ggtcgcggcc gaggtactat tgctctggct cctggccctc tccttgctat gggtcttacc 60 ctcaagtcgc tctgtgattc aaagatgaac tgccaatcaa atgttcctct aatgaaagat 120 ccaatcactc tacagcatgt gtgtattcaa agaacctatc taagactttc ttttggtcat 180 ggtgggaggc tgttgctgaa aacataccag agcccattgt ggaggtcagc tgacaggccg 240 catgaccttg gcaatggact actggtcatc tgggactgct taggactgtg caatggaact 300 tgggggcaaa actgatggag acagccaatg ggccttaaat ccagcaggca aagacagagt 360 aagttcttat ttgtgtagcc cagggcttat caaagtgtgg ttcttggacc acgtgcatca 420 gtatcagctg taagtatttg gcaaaatgca gattcccggg ccctgcacca aacagattga 480 ctttgaatct ctgggggttg ggctaaaaaa aaagaaaaaa aaaccctaca ttttaaacaa 540 gctcttcaga tgacccttgt gtaagtttga gagcatctgc tggaaaacca ctagaatttg 600 caaacggcca cctcaaaata ctccagccag tcccactaag ccaaagactt tcttttggtc 660 atggtgggag gctgttgctg aaaacatacc agagcccatt gtggaggtca gctgacaggc 720 cgcatgacct tggcaatgga ctactggtca tctgggactg cttaggactg tgcaatggaa 780 cttgggggca aaactgatgg agacagccaa tgggccttaa atccagcagg caaagacaga 840 gtaagttctt atttgtgtag cccagggctt atcaaagtgt ggttcttgga ccacgtgcat 900 cagtatcagc tgtaagtatt tggcaaaatg cagattcccg ggccctgcac caaacagatt 960 gactttgaat ctctgggggt tgggctaaaa aaaaaaa 997 11 696 DNA Homo sapien 11 gccgcccggg caggtacaaa tggtgcccat gccattcatt tgactgtggg tggccctcta 60 gtctagggct ctcttagtga atggttgtgg aaatatgatt tttctaagtt ccttcctttt 120 ccttttgata gatgagtttg agatgatgga gtaggagtga ggccctcagg cacttctggt 180 aaagacattc cacctgcaag cagcattttg agtaaagcac tgctgtggtt tgccgattta 240 tggtccattt aatgttaggc taaagcacct ttaatcattt ttgttgtttt aagataatgt 300 atttgtgaag tggataaaca ctggaaatag ggtgcttctt ctggaaagtt cagtgtaaaa 360 cactaacaag gctttggcgg gtttatctgg ctttataaac aagtctgaaa aatggatgaa 420 agctaaatat ataaagcagt tggttgtcta tcttttatca ttttttactc agatctgtat 480 ttaacactta tttatttgtt agtttttaca ttcaaaagaa actacacttg gaactttggc 540 taacattgta ggatattttt taattgttcc tacattttta agcatgattc atcattttgg 600 taacttagat catttttaat ggtcttttct ttcaataacc agttacatca tgttttggga 660 actctttggt tccatataag gtgaattggt gcaaaa 696 12 3233 DNA Homo sapien 12 aacggtccta aggtagcgag agaatactac caggtgctag tttttccagt attgacttct 60 gattactatt tccttttctc atctttagtt tttcaagatt tgctttacca aaatagtaaa 120 gcctttatca tcagcttata ttgaataatg ttgtaattgg tttcaatcaa agtttctcct 180 caggtacttg ggggccccta gccttctaag gaactcccag gcacctactt aacaaggcca 240 gctacacact cagtatgtga taagccccat gatggatgca ggttagaatt caaagacctg 300 gttggagtcc tagatgtgga gacaggatca tcaggtcaca cttgttagat gactaacact 360 atcagtagaa gctcttgaga gattttccta acgcagcaag atttctgtga gtagaggtat 420 cctgggaggt atcctgggag gcagcctatt gacttgacca agtaagctga tcaggtggcc 480 tcctctaccc actaaagaaa tgtgtaaaca ctagcaataa ttgctttatc ttaaactcct 540 ggacatactc agttcctcca ttccactgtt ctattgccaa tacctttgtt gttttcttca 600 cactcctctt ggcagcaaat gtctgaaagt atttcaattg tgtaatgtta aggagttttt 660 tcatagcttc agaaaagagg gcagcaaata tgaagcctta agttcaaaat aagtcattct 720 acctagaaat acagacccca gagcacattg catgaaaata cctgtactct gcagttcctc 780 aaagcagtat tcttcctgaa aagccaaaca ccacacctat tttcctattt gctaagaatc 840 agaataagca cgttgtaaat agtatccaaa gcagattcta aaatgacata gtaagaagcc 900 agattcaaat tgtaaccaaa gaagacaata gaaatcccac tttaccccac tgtcatcagt 960 tagaacaccc ttgcaaaaac tgtaaccact taagcaattc atctgatccc agaagatcat 1020 accttctttt gaaagtatag gacagatatc agtgggaaac gtcggcgttc tgagcaacac 1080 aggataaatg taggagggcc ttaaaaaata aatctcaatt catacactgg agcagcaaaa 1140 aactgagcag gaaaggaaac agaatccaaa gtcatttttc atatagctgt tgtcaaatag 1200 tataaccttg gtgtcttctt tgagttgcct ggacagtatt tatgaaacaa aaaactaaat 1260 gccccccatt tggggacggg gggaggggtt cagacctcta acctggattc agagccttag 1320 aggccgagag ggaatctgga atctggtatt actgagatcc taggtaaaag aaccagcctg 1380 gcagtctttc ccacctcatt ggtccgtgct tttattttta aacccaaaaa aaaaaaaaaa 1440 acacaccctc ttatgtagga atttcccttt tacaaataat ttgacctggt agaaataaac 1500 ttgcctgcct gctcttaaat gccagacagt tggaagcaaa tgccgaggga aaggtgccca 1560 gagccatgct tgataggact ttgaatattt tctccttaat taaagtacgt tgcttgtatt 1620 tagactataa gatgctatgg aggtctatcc catgccatgc caatgtgaat tgctttgctt 1680 cagtaacaat cagaagacca gtccaacaga aaataacttg tcataattcc accttagatt 1740 ctagacctct catacctgca gtgtacagaa tatgtacatg ttccaatgga attcactatt 1800 tttggcttta gtgtcaaaga gattggttct acaaggttca tctgatttcc cataacaagt 1860 aaattttata atcctatgat tctaaattca atccccaata tagattctaa gcatcaaatc 1920 aaaatcacag acaaagggga actggtcgag aggggtctta gttatttcaa atccatgacc 1980 aaagtgtcca aagacatgaa actcttatac ctgctgagca tttcacttta ctatacaaaa 2040 tgtcagctac ccagttgcat cctgtgacat gatcagactg tcaatgtgga ccagtggcca 2100 ggagcatatt tatgggccat ttctgttcat cattctttac agagcattga ggtttcccac 2160 tgaaacagct tctttagtca gacgtctata gattttacat aaatttacat ttaaatgcat 2220 taagttagat ggcccaattg agcatctgaa tgaatatagt gggggttggt ggtggtgcaa 2280 attctgctgg ctttatgtta tggttttctt cgtgtttttt cttggttttg tctggcttct 2340 tctggcaagt gccctaaaag actggaacac tgtataaagt catagacata gaaccatatg 2400 ggaaagccca gatgaaaaaa tggaagaata aaatcaagtt gtcaaagttc cagcaacagc 2460 cctgacttct tcaggaatcc aagcaaattg aaagccaaga caaaatgtac aaatggtgcc 2520 catgccattc atttgactgt gggtggccct ctagtctagg gctctcttag tgaatggttg 2580 tggaaatatg atttttctaa gttccttcct tttccttttg atagatgagt ttgagatgat 2640 ggagtaggag tggggccctc aggcacttct ggtaaagaca ttccacctgc aagcagcatt 2700 ttgagtaaag cactgctgtg gtttgccgat ttatggtcca tttaatgtta ggctaaagca 2760 cctttaatca tttttgttgt tttaagataa tgtatttgtg aagtggataa acactggaaa 2820 tagggtgctt cttctggaaa gttcagtgta aaacacaaac aaggctttgg cgggtttatc 2880 tggctttata aacaagtctg aaaaatggat gaaagctaaa tatataaagc agttggttgt 2940 ctatctttta tcatttttac tcagatctgt atttaacact tatttatttg ttagttttta 3000 cattcaaaag aaatacactt tgaactttgg ctaacattgt aggatatttt ttaattgttt 3060 ctacattttt aaagcatgat tcatcatttt tgtaaactta gatcattttt taattgtctt 3120 ttcttttcca atagaccagt taccactcat gtgtctgcag aacctcttta ttgtattcct 3180 ataataaatg taaaatattt gtagcaaaaa aaaaaaaaaa aaaaaactcg gtc 3233 13 847 DNA Homo sapien 13 actagactat gatatggact taccctcttg gtgccagccc tacaagctgc atgaccgtaa 60 tcagcctgtg acactacgac atgcgccact cagcctgtgc cactcttggc ctgagccttc 120 ggcctcttat gactgaggcg gacaactcac gctcaacaat ggcaaagact gctgcaccat 180 tgctagatca catcaatggt gccaccaact actctcttct tcacctacca acagtggact 240 gactggcttc tatgactcct atccacctca tctgctcccc tagtcacgaa ctacaagaca 300 ccacacaccc ccagccgcag cgcgaatgcc aaaggttcag cacacacggt gcgcaaacaa 360 cccaatgcgc gacccatcat catccataca tatctggcgc tgctacgcgg acctacctac 420 gccatgtcgc tcctgactac tctgctccac tgatggctcc tcctaccaac acgcgcttgg 480 ctcctgccag cctgcagccc acacacctgc gccctccctt ggcacgacac ccactcaccg 540 ccgactgccg aacgcaccag ctgacggaca cacgtccact ccacccgcgc ccaatcacct 600 cgcgcacgcc ccagcccttg ccctcccata cccacggcct acaccacacg cgcccacctc 660 acactgcgac cggctgccca tatctctcca cgtcccgccc tctgcccccc ctccacacac 720 gcagcatcca cccagacaac ccacactgca cgacccctca tcacagcccc tcaaagccct 780 ccaccaccac acaccagcag tcccccgccc caacacctaa taaaccccac ccccgccgag 840 cctcaca 847 14 267 DNA Homo sapien 14 actgtagcag tgagctcaag tgttgggtgt atcagctcaa aacaccatgt gatgccaatc 60 atctccacag gagcaatttg tttaccaaga atctaagaat taaatcttag aatgtattaa 120 tgttaaattt ctgtgagatt atattgtagt cacgtagaat gtcctgactt gtaggaatac 180 ccactaagga aatcagaaat cacggtagag cgtcagcaat ttactctcaa atggttcaga 240 gaaagaaagt tctttgtagt aaagctt 267 15 824 DNA Homo sapien 15 tggtcgcggc cgaggtacag tgggtggaaa gggcatttgg agctcattag aatgagacat 60 agttaagagt cccattctca tcagtgtatt ccagactgag gaagaaatgg ggcagcagtc 120 aggagagctc gggattttga gtatagcaga atttaagtga aatggaaact acactcttta 180 atttgttctt ccatggaatt gctttttcta tgcaagggct gagcccccag gagagccctt 240 gtgaagggaa tgctgatttg tgtgaatatc tgtaggtgag taggtatcta gtgaggatga 300 gttgggagga tgagttgggt aaggcgtgcc cctctgacac tgttctgggt ataaaagaca 360 acatcatgat gagatcttca tctgaataaa actatgccct ggccttttca gaaactgcgg 420 gcactgcagg tcccacagtg tgatggagtc caagctggga tcactgcgag atgaggagtc 480 agaggagtgg cttcggcagg catgggagct tcaggccctg agagagaaga cagaaattca 540 gaaaacggag tggaaaagaa aaacgtgaag gaactgcatg aagagcacat ggctgagaag 600 aaagagctac aggaggagaa ccagaggctc cagggcctcc ctgtctcagg atcagaagaa 660 ggcaggctgc cagttccaag tgccagatca agcaccctcc gtgccagctg caggaacgag 720 ctaggatcat tgcttccagg aggagagacc agccttggtc tcaaggaagg gcaccggacc 780 aaaggggcaa gggggggaca cagagaggat ccacaggaaa aatg 824 16 1998 DNA Homo sapien 16 tttactttta ttaaagtata ggaatcaaac tggataccaa attctcagtg cagttgggta 60 gtcattttgt taatgtattt ttaaaaaatt ttaagggtaa aaaccagcaa gattccattt 120 agaatgattg tgaaaaaaac actgtaagac gtccattttc aaaatgcaaa aaatgattct 180 tcctgatgtt aggaaggcca atgaaaacta tatgtatatt gaaaatattt tttcctcaaa 240 actttttccc tgatacagaa gtctgagagc ttactttggc tacattacct gactaaagag 300 agaactttag attagacctg gggtaaattg agatgccaag ggagtgtcta gctaaatgga 360 aataccacga aggtttgtaa tgccaagaaa gtcagctctg tggtgtgtca taagcagcat 420 atggaaacca ggagtgacac attagaaccc gggagttgtg catacatctg atcaagcatt 480 tgactctgaa aatattcagg gagtttagaa attgttaacc tttggaacca gtattgttta 540 gcaatagttg agaagtgtta gcaagaatga tatcaagtta aacttaggca cttggagtta 600 catccttaaa gccttaatag ggcttatgag ttttatacag tcatacagat agaaatatgt 660 tgcttttgtt actacgacag tcatatatta taagaaataa tcaaaggtgg gtggaaaggc 720 atcctctctt tgatccaatt ttctgtacct ttttcttcag gtcacacaca ctgctagccc 780 aggaatcact aggtattgat gactctactt caagctgtgc aaagcccttt ctggagacag 840 ccaggatgtt ttgtagggag agaggcagga gtcctcaggg agtggcctgg ggtgagaccc 900 tcccataggc tctaagagtc tcattctcat cagtgtattc cagactgagg aagaaatggg 960 gcagcagtca ggagagctcg ggatttatga gtatagcaga atttaagtga aatggaaact 1020 acactcttta atttgttctt ccatggaatt gctttttcta tgcaagggct gagcccccag 1080 gagagccctt gtagaaggga atgctgattt gtgtgaatat ctgtaggtga gtaggtatct 1140 agtgaggatg agttgggagg atgagttggg taaggcgtgc ccctctgaca ctgattctgg 1200 gataataaaa gacaacatca tgatgagatc ttcatcatga aataaaacta tgccctggcc 1260 ttttcagaaa ctgcgggcac tgcaggtccc acagtgtgat ggagtccaag ctgggatcac 1320 tgcgagatga ggagtcagag gagtggcttc ggcaggcatg ggagcttcag gccctgagag 1380 agaagacaga aattcagaaa acggagtgga aaagaaaaac gtgaaggaac tgcatgaaga 1440 gcacatggct gagaagaaag agctacagga ggagaaccag aggctccagg gcctccctgt 1500 ctcaggatca gaagaaggca ggctgcccag tcccagtgcc agatcagcac cctccgtgcc 1560 cagctgcagg aacaagctag gatcattgcc tcccaggagg agatgatcca gtccttgtct 1620 ctcaggaagg tggaagggat ccacaaggtg ccaaaggctg tggacacaga ggaggactct 1680 ccagaggaag agatggagga ctcccaggat gaacagcaca aggtgctggc agctctgagg 1740 cgtaacccca ctttgctgaa gcacttcaga ccaatcctgg aggacaccct ggaagagaag 1800 ctcgaaagca tggggataag gaaggatgca aagggaatct cgattcagac tctcagacac 1860 ctggaatccc tgctgagagt ccagcgggag cagaaggccc ggaagttttc tgaatttctg 1920 agtctgaggg gaaagcttgt caaggaagtc accagcagag cgaaggagag acaggagaat 1980 ggcgctgtgg tgtcccag 1998 17 653 DNA Homo sapien 17 gcgtggtcgc cggcgaggta catggccgca agcagactaa cgcgttgacg ctaatttaat 60 gtattttacc tcacactaag gtcatgcttg ataaagacgt taaactcaac ttgtaaaatg 120 gtagcccagt gctatgcaca gagtgggtgc tcattagtgt tgaatgaaca catttgtaat 180 actacatgta attccatctg actgctttgt taaattttca gttagaacgt agatactgta 240 aagtccacac acacattaaa tcttgttttc ctgaaagtat ggcatcaaaa atacttgtag 300 aaaaaccttg tcacaactga tttgaatgtt cctattttct ttgactttga tattggcttg 360 taatgtctct tttcatcata tgtaatatca gtggaacagg cagcgctact caagtcctaa 420 ggattcctca gtgatcagtg atccagggcc gttcatgaac cactgggctg gatttgactg 480 ttgagtgtgg cagttaatgc ccctcaagaa atcaaaggat gtcttataag tgtcttccaa 540 aaaaaagcaa atgctgaaat cctattggca aagtaaactg aaattggctg ctatatttta 600 tataatcatt tctgcaaatc ccattttttg aatactaata tttgacatgg tta 653 18 1498 DNA Homo sapien misc_feature (29)..(29) a, c, g or t 18 ttattcagtg catagcttta agccagtgnt ggattcacta agtggacagc cagtctccca 60 gctctctgcc ttccccaaaa gggtcgtagt aggtcaccct tctacagcag ctaactagag 120 tcctaactaa tgggatccag cagggccatt tctccagagg gccagtatcc tattaggaga 180 ctcttggaat tcttaggttc tactcaagag tggaaggacc aatcacctct gatattctgt 240 ggaaggtttg gggtcaaatt ctgccctctg cattctgtgc aacttgtata aaagtcaagt 300 tagtattaca tgaattgggg tagggttagt gctttgaaaa aatgttgaac cggctgggcg 360 cggtggctca cgtctgtaat cccagcactt tgggaggccg aggcgggtgg atcatgaggt 420 caggagttcg agaccagcct ggccaacata tagttgcttt ggacctcatt tggaaaaata 480 atctgccttt ctaattgttc tgcataggtt aaaatgataa atttacattc tttgaaccta 540 taccagattg tggtgtccga gtgaccggca cactgtctga cacacagtca gtgtgcacgt 600 atttgtctga gtgaatgagg agacctgaga aaccggtgac gtggcacagg gaagccagct 660 ggcccaggat tccgtacatg gccgcaagca gactaacgcg ttgacgctaa tttaatgtat 720 tttacctcac actaaggtca tgcttgataa agacgttaaa ctcaacttgt aaaatggtag 780 cccagtgcta tgccaggagt gggtgctcat tagtgttgaa tgaacacatt tgtaatacta 840 catgtaattc catctgactg ctttgttaaa ttttcagtta gaacgtagat actgtaaagt 900 ccacacacac attaaatctt gttttcctga aagtatggca tcaaaaatac ttgtagaaaa 960 accttgtcac aactgatttg aatgttccta ttttctttga cttagatatt ggcttgtaat 1020 gtctcttttc atcatatgta atatcagtgg aacaggcagc gctactcaag tcctaaggat 1080 tcctcagtga tcagtgatcc agggccgttc atgaaccact gggctggatt tgactgttga 1140 gtgtggcagt taatgcccct caagaaatca aaggatgtct tataagtgtc ttccaaaaaa 1200 aagcaaatgc tgaaatccta ttggcaaagt aaactgaaat tggctgctat attttatata 1260 atcatttctg caaatcccat tttttgaata ctaatatttg acatggttaa ttcttattaa 1320 tttgttggaa ttgtttattg ttaataatgc aaatagataa tttttaatta tccacaactg 1380 atttgaatgt tcctattttc tttgactttg atattggctt gtaatgtctc ttttcatcat 1440 atgtaatatc agtggaacag gcagcgctac tcaagtccta aggattcctc agtgatca 1498 19 171 DNA Homo sapien 19 gccgcccggg caggtactaa atgaaacata atatttattt ataaaagtgt gtagattgtt 60 aaatcacaaa aagagtgcta tgaccattat gtatgaggaa acaggccttt gacctcctgg 120 aaagcactgc tcaaaagtca ttagtgccca tttttgaatt ccccaaacag a 171 20 1820 DNA Homo sapien 20 gaatttcgta atccttgaaa ttgaaaaaaa aaaaattgtg tttttaaaga gtgaaaacag 60 ttaggaaaca agtagaactg taatcagaac gctgcttcaa ttgatattaa aaataacctc 120 aataataatg taaaggttcc tttctcttgt gtcagttata ttcttaggga tagcctagaa 180 ggaatatatg gttagaacta agtgtgacta atcatctgag ccttgaagag aaacttcagt 240 gcctctaaac agatcatcta caaaacaaca ggtaaacatt tatgccagtt aagtgggtca 300 tgtttttgtt tcttgggttt ttcctaaatt taagtgaggt tgggcttacc ttgtagataa 360 aattatgttt tctttttggt aaatacttga atgtggataa cgtcaaatca gaatattttg 420 tgaggaggtg atgatttgaa attaagctag atttctaggg aggtgttggt tccaatgaag 480 gatgggaaga aattaaaata gtcttcaaac ttcttcctta ttatatttgg ttgctttgga 540 aaagattggt cctatcctca atctaattta ttcactatta atattttaaa aacattcctg 600 agatacttaa aaagacccac ttagcgatta tagttgctca atgaaacaag aatttattta 660 tgcatagatt tttctctgta tcttaccaaa atccacttta cttagataac actaaattgt 720 tcttaaagac tactcatttc ccaataatcc tttatgattt caaaatttct agtggctcag 780 aagtgaattt tattttattt gtctttcact tgaataaatg agaacccaga aattaataat 840 gttgtttatt gcttactgtc aggactattt caaagactaa gaagagtttc ttctaacccc 900 tccctctcaa aggaatccta aattattagt tgttagataa gttttgtatg ctaagatatt 960 caggtttata gtttatgtat gtgtgtatat atataaatat atatgtatat ataaatatta 1020 tgttcagttt ggagtctggc acaactccat tatgtggatt agagagtaag atattatgga 1080 tgataaagta ctaaatgaaa cataatattt atttataaaa gtgtgtagat tgttaaatca 1140 caaaaagagt gctatgacca ttatgtatga ggaaacaggc ctttgacctc ctggaaagca 1200 ctgctcaaaa gtcattagtg cccatttttg aattccccaa acagaaagct tcttagaaaa 1260 cacgctgaga ttttatttac agggaattct ttgacacatt tcaattggtg tgtagtcaag 1320 tatagcaagt acttaataat gactgaattt catgttccta cagtcataca tattcattag 1380 aagttttatg ttgttggtct gatctgattc ttctttgttt gtgggtggaa cggcactgag 1440 agaagtatag ttttttaaac ttgaacatgt tcagtagtta cattgcctta gaaaacccag 1500 acacatagca gtggaaatga aagaaatggc atcagaagtg acttaattta gcaattgtga 1560 ttcctcttgt aaaacaaaac aaaaaaacaa tgccatattt tttggagaaa agttggcaat 1620 ataggggttt cgttgtctgt ttcacaagaa gactcatttg ttcttttggg ggaaccagtg 1680 ccttacagat tttgtatata ctgtaattat tcaggactag ggaacaaaca attgtattgt 1740 atttgttaca gattgtatat ggctttgttt taacattccc ctaaataaaa tggcttcatt 1800 ctccccttgg aaaaaaaaaa 1820 21 611 DNA Homo sapien 21 acccaagaca ggttctgaac catgcttatg cagagctttt agtattaaag agggagagta 60 aaagaagtgt cagagtccag atttatcact gaacccaata ctttcttact ccctggggca 120 tctcctaata ctgatcctaa aatgctcctg tttctgagaa gctagggcaa gacctgcctt 180 acaaagacca gccatttgcc ttattcatag gatcataagc aagagaactg cattccagga 240 agaatgaagg aagaaggaag gctgctcaca gtagcagaag ggaggcaggg gccgagctgt 300 tcaagtcaca taaactctaa gaagcccagt cagcaaaata agtctatctt caattctagt 360 tgagtccagg actctgagga gctgtgattc acccagtttt tcctgcaaaa ggcacagtcg 420 ctaaactaaa ttggtgcaat tcacttcctc ttgcctctct ggttcattcc accaattgtg 480 gttgagaaac acatcttagg gaagaaacag tatctaagca ttaaagagaa aatatcccac 540 tttgctcctc ttcctcccta aacccgaact gctcttacat acaagataat ttttaaatca 600 taagattggt a 611 22 1885 DNA Homo sapien 22 catgaacatt tgaggctgat tccctgtggg aaaaatcatt caaatctatt cactcatctg 60 atggctgttg cttgttttat tttttgtcca agagaggtgg tgttggaccg aggtagagaa 120 gacagtggta caccagaaat aacccaaagg attgcccctt ctgtagaagg cccttagact 180 ccatgatgcc tttcagctgg gtgctatact tgcacctaac tctgggggct tcactttcta 240 tccctacaat tactcaaaca gataaaaggc tggatgttaa catgtagtta taaggggcgt 300 gatctaatag taaggaatat cacttcccac aagtccttca aacaagattt gtgaggagct 360 ggatttgtca gcatgtcaga tctttttgaa aaccagagag tagaatgtaa gcaataccct 420 tgtcgtaatt aaagaccaga ctccatcctt ataccactga tgcctctggt accttaatcc 480 ttaaaatatt tagtgaccct tgccttctaa ttcttgacac aaatatataa tgaccatttt 540 agatcgggga actccctttc tttgaaggca gtttagggat tccacagatg ggctttgaac 600 ctgctaaatg tgtatggaaa actgagtgaa ttacaaatgt ctttttctca aaagtgcgtt 660 tctggtttct gtcagattca acaggtctgt acccaagaca ggttctgaac cactgcttat 720 gcagagcttt tagtattaaa gagggagagt aaaagaagtg tcagagtcca gatttatcac 780 tgaacccaat actttcttac tccctggggc atctcctaat actgatccta aaatgctcct 840 gtttctgaga agctagggca agacctgcct tacaaagact agccattttg ccttattcat 900 aggatcataa gcaagagaac tgcattccag gaagaatgaa ggaagaagga aggctgctca 960 cagtagcaga agggaggcag gggccaagct gttcaagtca cataaactct aagaagccca 1020 gtcagcaaaa taagtctatc ttcaattcta gttgagtcca ggactctgag gagctgtgat 1080 tcacccagtt tttcctgcaa aaggcacagt cgctaaacta aattggtgca attcacttcc 1140 tcttgcctct ctggttcatt ccaccaattg tggttgagaa acacatctta gggaagaaac 1200 agtatctaag cattaaagag aaaatatccc actttgctcc tcttcctccc taaccccgaa 1260 ctgctcttac atacaagata atttttaaat tataagattg gtattaacac aattattgat 1320 aaagagaaac aatgaccaac tcattagcta acgatgctag aatacttatg caagccctag 1380 agttaagggt cttagtgtgg acacctttcc agaattggaa ggaaaaccaa ccagaaagct 1440 tattaccctg catcagctga aaagctaagc cacagccatt ttccctaaag ttctgtttct 1500 gggagaatga gatcttcaag aataactctt gccccttgat gaggcagtca aattcaaacc 1560 agtgatggca acaacttgca aacacgtaat tcctgcccta attttccagc acttaaaaca 1620 aaatccccac tcaatacaaa gtttctatgt gcctcttgcc tgaaatcaac aagaaacagc 1680 tcacctgccc aaagactcct ctttctctgc cagggcaaaa gcaatctgca gcccagagat 1740 tcaaacctag acatacacat ccacaattgt cttaatctca gcagtactgg gaaagctttg 1800 tactcaactt aacctgtcat ttaacccttt ccactagttc tcccttaacc agactgcttc 1860 ctgtcttgaa acaaagaaaa aaccc 1885 23 494 DNA Homo sapien 23 aagcgcgcgc attgtgatgg atctatattt taccctgtgc ttttctatag ctgtcctcaa 60 agcgtaaacc attccaaatt attttccaac gtagtgttat atgtgtgcag cagagctatt 120 tctgcctggg cattgccagt ccctgagcag gagggtctca cagtgaggtc tgcaggactg 180 taagtttggg gtctgactcc ctggccaccc tgtgtgggct gtgactgtct ctcagagcta 240 tacccgccct ttctctgctg gcagcccgac agagctggct caaccatcgg aggtcgcagg 300 ccaccagcca cgtggcacca ccatggcagc cttccaggtg aaggtgagac acacaaggca 360 tgacctgggg gccgaccgga tccccatcac aaacgccaca aacaccataa acacaaccca 420 ccctgatcag agactaagca gagaaagcag ggagaggacc tagagttact cagtaatgac 480 tcaggaagga gacc 494 24 1692 DNA Homo sapien 24 gtcccccacc atggaagagg ccgggcccac ccactgcaag tcttctctga gccacgttct 60 caagtcttct ctgagccgcg ttctccaggt tgtgctgctg gagtcagttg gcatttcctc 120 caagcctgaa agtgtagtca gattcagaat gggcttttct agattcccct gtaagatctt 180 tcccctgctc ctggcaggag caccacacca tgggaacccc agggcccacg cagctgcccg 240 ggactggggg accaggacgt ggcacttctc acatgggtgg aaagatgggt ttacagaatg 300 gtggcatgga gacgctgtgg cctggcaagg atcaatgggg tggcatctgg cattagccat 360 caggaagact taaggctgaa gggacattgg gcagggagct ctcagggctg ctccacccgc 420 ccccagggtg acagcccata gtatcactta gggtgggact gagagtcacc tgggggagag 480 gagagaaggg gcccaacttc cccagcccct agtatcactt agggtgggac tgagagtcac 540 ctgggggaga ggagagaagg gacccaactt ccccagcccc tggcaccttc cctgcctttc 600 ccagtctttt accagagtca taagatggtc cttggctctg ggcaggcatg tggccctggg 660 gagctctggg gtcagaggtc aaggtgcttt gcatgtcagg caggcttgac ttttgcctgt 720 agaaagacta tagaaagatg gcaagctagg cctcttttct ggaaaagtgc caacagctga 780 taattttagg aaataatgtt ttgaatgtga agtgtgactt tttagaataa aaagacagga 840 agctcttaga aactgcaaga ttctaaatct aagcaaaagg ctatatttta ccctgtgctt 900 ttctatagct gtcctcaaag cgtaaaccat tccaaattat tttcaactag tgttatatgt 960 gttcagcaga gctatttctg cctgggcatt gccagtccct gagcaggagg gtctcacagt 1020 gaggtctgca ggactgtaag tttggggtct gactccctgg ccaccctgtg tgggctgtga 1080 ctgtctctca gagctatacc cgccctttct ctgctggcag cccgacagag ctggctcaac 1140 catcggaggt cgcaggccac cagcccgtgg cccacctggc agccttccag gtgaaggtga 1200 gacaaacaag gcatgacctg ggggccgccc ggctccccat cacaaacgcc acaaacacca 1260 caaacacaac ccaccctgat cagagactaa gcagagaaag cagggagagg acctagagtt 1320 actcagtaat gactcaggaa ggagacccta agcttctacc acatgccaga ctctgtgccc 1380 agtgcagcat aaacgtcctc agaaccagcc tggtcccagc ctggccgagc cggacgttcc 1440 tgggaaaggt tacaggagga gcagggccag gcccacagca cttttagaag cccatgaaaa 1500 tgtcttcatt tctcttcaaa tcacaaacaa aacgtgcaaa acccattctg gagtgcatct 1560 tttcactggc gaccaaccca gtcctaagat aaccttctta atagttctat ggaggaagct 1620 gcaaaggcag aagtgactac aacccacaaa agtcatgatg gagccctgac gtgtgtgtac 1680 acacacacta ca 1692 25 430 DNA Homo sapien 25 acccagcgtc ccctggccag agccaccaga ggacagagct cccaatgagc ccagctgcta 60 gaaaagaagg tggagtccca ggcagaagag ttcttcaggc tgaacggaaa tgattccaga 120 gggaaatgca gatatgaaga aggagataaa gagctccaga aatggcaaat agcagggtga 180 gcctacgcga cttctctaac ggaagaaatt acctttaaaa cacacgtgca ggcttagagc 240 aaaagaaacc gtgccataag gtgtgagtaa gtgaagtgcc tgtgacacct acagatcaga 300 gaagcagagg cctccgggat ggcaaggcaa ggttgccgca tttcatatga agtgcacaat 360 catcataaaa gaatgcatta aatatacata tgtatgcatt caaattacac taacatcaca 420 tatatccatt 430 26 2603 DNA Homo sapien 26 tgtttggtcc agtgaatctg cccaccaaca ccccgcctct caccatccac cagcccttgg 60 acccctagca ctgagctcac agtgaaaggg aatatttgct tgtaaataga aatagacgct 120 ggttagaaac caactggaaa gaatctttcg ttgaatagga gttaaaaaac aaggaaatta 180 acccactcct gggtatttct gaaactggca atctatgctt gtctaggacg gcccagacta 240 accctaatcg ccccgtcatc aacacagcag cacagcgttt cctccaggag aaacaccaag 300 atctcacgtc ccatccacag gctgaggctg ctgctcctgc aggaacctgg tgcagtgtag 360 caattccaca tcctgaaatt gctcatcaaa actcctatta aagtgtcaaa cagtgaatag 420 ctaaaatacc actttgcttg aacagtgaag aggttggaag gaaaacgtta actgtatcag 480 agaatatgga ctcctaacat acagggagtc aggttcattt tgaagtcact cttcttccaa 540 cagattcact aaggctcttt gtcaacacaa attgaaaacc gttaaaaaaa aaagtaatta 600 tgatgcttcc tgccctccat gaaaggacca catacagaca ccacgctcat atctgaggcc 660 ctggggtagc ctttaatggc ccagcagaat ggccagaacc gttagaggaa acatttaata 720 aagtctggag tcagagccct gcgggtctag ctggattcct ggaggtgcgg cccagaagcc 780 agcgggaggg aattggaggc cggaggctca aactgtcccc acttccacca agggcccctc 840 ctccaacagc ttccaggctg ccaaagcccc tgcatcacct ccagggtccc ctgggtccag 900 cctcatgctt cccataatga gtttttaaac cacaacgctg catcaggtga catctcttct 960 gcaggctgtg cgcgtctcca gggggaaggg ggctgtgtct ttgggacagt ttgtgctctc 1020 aatcacttga ctgctgacag gcacctcagc tgaatggtgt gatttatgca aagattgtgc 1080 tgaattattt aaagcattct ctatttaaag aacagagaat atttaattag cattctgctg 1140 tgcttaattg aagactcaca aatcaattaa aactgcttac cttttggcag ttcagtaact 1200 tcacagaaac ctcccaggaa atgcatccta ttcacagctg ggttcatcct atacccagcg 1260 acctgtggcc agtgtggcgc tgtgattaga ggcggctcag cgccttcaga ggagcggcct 1320 ggctgtgcgc acattagaga aaggcttcca tcgtcgttgg tcctctttct cacagggact 1380 ctggggtctt ggtgccggga gatgcaaccg cctctggcag cccggcttca ttttagggac 1440 agtgactatg gagaaaccca ggtctgaccc attttctcca gaggggaggg agccacaggg 1500 aaaggcccct tgttgctctg ttggccctga gtgcctccca ggaaaggtca gagcacagac 1560 tcagccctgg gagggccgag agatcccgct ggaccctgcc ctcctcgaca ctctggacaa 1620 gatgcagaga gtggggtcct ggcagcaaga tcccgtggga gtggggcctt ggagctcagg 1680 gccagaccga gggggtgctc attgctggct ctggcctaca gacacgttga cattggcacc 1740 acacgggcca actgaaaccc taagagaaaa cccagcgtcc cctggccaga gccaccagag 1800 gacagagctc ccaatgagcc cagctgctag aaaagaaggt ggagtcccag gcagaagagt 1860 tcttcaggct gaatggaaat gattccagag ggaaatgcag atatgaagaa ggagataaag 1920 agctccagaa atggcaaata gcagggtgag cctacgcgac ttctctaacg gaagaaatta 1980 cctttaaaac acacgtgcag gcttagagca aaagaaaccg tgccataagg tgtgagtaag 2040 tgaagtgcct gtgacaccca cagatcagag aagcagaggc ctccgggatg gcaaggcaag 2100 gttgccgcat ttcatatgaa gtgcacaatc atcataaaag aatgcattaa atatacatat 2160 gtatgcattc aaattacact aacatcacat atatccatta gactttatca aaattaaaat 2220 cttctgttca tccacataaa acgatgtcac ttactgcaaa aaatattctc aaatatttat 2280 ccaagtgctg agatccagaa taagtaaccc ctaaaatttc ataataaaac aacttggtga 2340 aacaacggtc aaaggatttg aacacttcgc caaatgatgg caaataaaca caagaaaaag 2400 tgctcgacag actcgagcac caggaagatg cgtcgtaaac accaacaaaa accaccacac 2460 acacccacag tagccaaaat ctataaaact ggtggcacca aacgtgaggg aggatgtggc 2520 ccacccagca ctgttgctgt gcattcttgg tgagaacacc taagacgtcc cctcaatggg 2580 attagaaaac cacaaggcag gca 2603 27 614 DNA Homo sapien 27 acatatattt aaagggaaga tggatacaat ttgtttttat tatataaatc taggtaaggt 60 gaaatgcttt tgtcaacaaa aatacagtgt agtgaatttt atatttgtcg cttgattagg 120 taaactgaaa actaacaata gaaatattat tttactgcat tgaaatacca tgaactttca 180 gacttgttag ttctacaagc agttgtgcta ccttaatttt gtgtttccag aaataaaaat 240 taaccttagt tatgctgtca tttttaacta ataaaaaaag tataattcat aaaacttttg 300 gctttataag ataattataa aattatatat ttttttctgt ttttgtgggg ttgggaaaac 360 attttcttat ttctattcac tcttcaaatg caggtctcat aatatgtgtc aatgatataa 420 gatgatggaa gacttctgta ataaaaacat atgtcattat cttcaatttg ttcaataaat 480 aatttaactg tgaaacaaca aaaaaaaaaa ccaaaaaaaa aaaaaaaaaa acaaaaaacg 540 ggggggggcc accggggcaa agggggcccc gggggaaggg ttcccgggca aatccccata 600 agagcaaaaa acat 614 28 1134 DNA Homo sapien 28 gcacgaggat tggtcaaagt agtattctct tgaagttcta gtcaatttaa tttgatccaa 60 taagtttttc tgaatctcct ttttaagttc caagaaattc tattataaat aagtgtactt 120 ttaccaattc cattgtataa gcaaacagac accttttaga aaaggataag taatcatcaa 180 tttgtttttt ttaaaaaaaa acaatttcca gactactaaa tttggcataa gaataattct 240 tttaaaatgc aacatacttt aattagtttt tttggtatat gcataagatg tgaactttcc 300 tattgatatc actttatatt aatagagatg tacatttctt tctatgccgt ggctagagca 360 aaagttaata atgattattt acacaattga tttaatttct taggatatgt ataatattgg 420 atattatatc tgatttaaaa atactattcc atacattttt tttttcagga gataaaacat 480 agggaaaggt tttcatgtga attctttgta tcactttgaa gtacatatat ttaaagggaa 540 gatggataca atttgttttt attatataaa tctaggtaag gtgaaatgct tttgtcaaca 600 aaaatacagt gtagtgaatt ttatatttgt cacttgatta ggtaaactga aaactaacaa 660 tagaaatatt attttactgc attgaaatac catgaacttt cagacttgtt agttctacaa 720 gcagttgtgc taccttaatt ttgtgtttcc agaaataaaa attaacctta gttatgctgt 780 catttttaac taataaaaaa agtataattc ataaaacttt tggctttata agataattat 840 aaaattatat atttttttct gtttttgtgg ggttgggaaa acattttctt atttctattc 900 actcttcaaa tgcaggtctc ataatatgtg tcaatgatat aagatgatgg aagactttgt 960 aataaaaaca tatgtcatta tcttcaattt gttcaataaa taatttaatg tgaaaaaaaa 1020 aaaaaaaaaa ccaaaaaaaa aaaaaaaaaa acaaaaaacg ggggggggcc accggggcaa 1080 agggggcccc gggggaaggg ttcccgggca aatccccata agagcaaaaa acat 1134 29 1139 DNA Homo sapien 29 cgaggtaccc attataatta ctaaactgtg aagtcactat tattagtatc tgaccagcta 60 tacaaaacat catcaatttt acttttgaca caaaaggtag taaaaatcgc aaacgataaa 120 gaagacacta ctcattaaaa gtcatgttta ctaatccagc accataattc cagtctcaga 180 acctcccatg cagattggaa agggattatg ggaacgaggt gagtatgtag gacatgtcgg 240 cgctagtaac atcaaattga cggccccata tttgctcgct tcacaagaca aaaaacacag 300 ggtcctccca aagtaagcag aagatgacat gacggcatgg agacgaaaaa caaaacgcta 360 gcgcgctaaa tcaatggtca atagctgcaa aaccatctga tgacaactag ggtaacttcc 420 cgtgtcaacc aaaaattcac aaacaagtaa gcactacctg tagaacagac acgaagtcac 480 gcaaacctac actttgagca cgcctgacca gagatccgag cacactcccc gacccaccaa 540 cacacagcag gccacgcggt agagagaaca agaatacaaa ggacaagcga gtagctgtag 600 aagcgatgag agagagcgta cgtagagatg ggggaggaac accacgtagg agcagaactg 660 ctgcactgcg tgcacacgcg acgcgaacag acgaaactac acgaagacaa aaggaaaagg 720 aaaggatggg accagagggg agagccaagc atgagagaca caccaaaagg cacccgcacg 780 ctgcatggcg aagcgagaag aacagcagat aaccacaaaa aaaagcacac acggtgggac 840 atacacacca gagggggagc atcagacaca gggacaaacc actaaagcag gagaacatgg 900 cgcgaaagga ctgaactaaa cagcacaaac acgcaacgag cagcgaacag ccgatcatag 960 gcgtgacacc cgactacagc aaaagaaacg gagaagttat cgacacaagg gatgacaagg 1020 aaacaggcta atggcccaag gagaggaaca ataagatgga tgagcacagt agggcgaaca 1080 agggataacc caagtgaaga aacagtgaag aagaggaatg cacacaataa gaacgcaaa 1139 30 235 DNA Homo sapien 30 agtgtttgca acagcaccat ttgtcaaatt caaagatgct caaaaggtgt tccctacttt 60 gcatgagagg gagagctttg taacaggaaa ttgtataagg caaactctct attcattcct 120 aaggcctctg ttcattccta atgtttacat ggttctctac tctgaagggc accaacatgg 180 acctcacctt cttaacatgg aaaatcaaaa tctaaatgaa ttaccattaa aagga 235 31 2171 DNA Homo sapien 31 ctgcattttt ctgtcattct cttcatttgt tttaaggtgg aaaattttct tacagttgat 60 gcaaagtatc aackacttta ccctaccttc tcccctttta gatgggttct tcctgagttt 120 tggagtcttg tatgattatc agtattcccc tgtcaaaatc aaatctattc aggtttcttc 180 actgttgaga acacctaaat gtttttattt ttgagaagtg gggacagagt ctcactatgt 240 cacccaggct ggagtgcaat ggcatgatct cagctcactg caaccttcgc ctcctgggkt 300 caagcgattc tcctgcctcc gcctcctgag tagctgggat tataggcacg caccaccacg 360 cccagytwwt tttttgtatt tagtagagac agagtttcac catgttggcc aggctggtct 420 tgaactcctg accttgtgat ccacccacct cggcctcccg agggtgctgg gattacaggc 480 atgagccacc acgcttggct aagaacacct aaatttttat gtttcttggc tcaaaaacca 540 gttccatttc taatgttgtc ctcacaagaa ggctaattgg tggtgagaca gcaggggagg 600 aggaagagct gtggtttgta acttgttcaa ctcaggcaat aagcgatttt agctttattt 660 aaagtcttct gtccagcttt aagcactttg taagacatgg ctgaaagtag cttttctatc 720 agaattgcag atagtcatgt tgggctaaca gtcaattgga tatattcctt tacctcacat 780 gaccccagca actgtggtgg tatctagagg tgaaacaggc aagtgaaatg gacacctctg 840 ctgtgaatgt tttagagaag gaaattcaaa aaatgttgta actgaaagca ctgttgaata 900 tgggtatcgg ctttcttttt cactttgact cttaacatta tcagtcaact tccacattaa 960 tgaaagttga ccatagttat ttccaaataa aaagaaacca actcttacca ggtcttggac 1020 tgtgatgtca tattattcag ttttatgctt gttcctgagc agaactcata agagtgacat 1080 agtcagctgc tgacggcacc tcagccacgc cactcttact cagttcagtg ggtgtgcttg 1140 cgtggtagga tgtggtgcag ccctctctac gctcttctat ttttggtata tttcctatct 1200 aaccttcaaa tagcttccaa ttcttttttt cttggactgg cttcattctg aatttgtgct 1260 aaaataatct ttcataaaga gacctcagtt tatagcgtaa cagactacac aatgcactga 1320 tgttttcata atgtttaagg gacccactgc aagaagcttg ctgcctcctt ttaattgtat 1380 tcatttagat tttgattttc catgttaaga aggtgaggtc catgttggtg cccttcagag 1440 tagagaacca tgtaaacatt aggaatgaac agaggcctta ggaatgaata gagagtttgc 1500 cttatacaat ttcctgttac aaagctctcc ctctcatgca aagtagggaa caccttttga 1560 gcatctttga atttgacaaa tggtgctgtt gcaaacactt tttttttgag atgaagtctc 1620 gcggttgtca cccgggctgg agtgcagtgg cgtgatctcg gctcactgca acttccacct 1680 cctgggttcc agccagttct cctgcctcag cctcccaagt agctgagatt acaggcgcct 1740 gccaccccac ctggctgatt tttgtaattt tagtagagac ggggtttcac catgttggcc 1800 aggctgatta actcctgacc tcaggtgatc cacctttctc ggctcccaaa gtgcttggga 1860 ttacgggtgt gagccaccgt gcccggcctg caaacacatt ttaattgaca acactagggc 1920 tgttgtacaa aatagtaatg atagccatgg aagttttacc ttattctgtg agaagtgttc 1980 ttaaacttat taaagtgtct aaaactaagg ttagtgcttc taaaggaagt ggccggttct 2040 cctaagaagc aattatcact gtccctgact ttgtctggtt ggtttggttc cccctgtccc 2100 cgattggctc tggtgtcctg ctttgccgcg gttcttttaa gccagcgcgg gttatttttt 2160 gaaaacctcg g 2171 32 192 DNA Homo sapien 32 gcgtggcgcg gccgaggtac tgtctctaca gccattgaga agccattcag tgccctggta 60 gggacctgag actttccaga attcacacag cagtctatga tccctcaaat gtaagaggac 120 agggggtcag cctatcttca cctctcagtg aatgtggagg gccaagcaat atgacttgca 180 aacctaagct ag 192 33 2641 DNA Homo sapien 33 tttttttttt ttcttttcca agttatttaa tttacagcat cagtctccaa atataataat 60 attaagatag cagtttagaa attaactttt tttcagatca ctctaacata aaatctctca 120 actgaatctc tagtttgtct cattttgtta agagctttaa tattacatgg gaagttcaga 180 gacttctatt tccatccctc aacatgtagt gacagtcaac atgtcaggct ctgtagcacc 240 gtgatatccc agcaccagac cactccagcc accctctcat tcaaagaagg gctacaagat 300 atggctggac tactcgaatc acatctgatc ttaatcaatc caggtataga aagttgtact 360 ataaagaata ctttccaaaa ttgttcactc aaataaaaac agatcaagtc attacagagc 420 atttttccat tttaataaga ataacagacc tactcaaggt aattttattc tgtttattta 480 aataaggata agactactta aaagactttt tacatacaaa aatgtacaag gttaaacttt 540 tctgtactga attacaaaac ctgcacaagc atgtaataaa agagcacact taaaaacatt 600 ctgaccatta tttagcctct aaaaattact gaagttcaac agtagtaaat agaggaagct 660 cttacatata tatatatata tatatatata tatatgattt aatctactgg cagttttact 720 taatgtaagt atttaaaagg tcacattgct attgaatgag tctctagatc aattttagaa 780 ttgtctctca aaacttaagt caaccaaaat attatttcaa atagtaattc caattctgaa 840 gaattttaat accagcaaat atattatggc ctcatagtag taactgaacc aactttccaa 900 agtgcctggt agctgtccag atgaattagg ctgctttgga aaactgtact gtctctacag 960 ccattgagaa gccattcagt gccctggtag ggacctgaga ctttccagaa ttcacacagc 1020 agtctatgat ccctcaaatg taagaggaca gggggtcagc ctatcttcac ctctcagtga 1080 atgtggaggg ccaagcaata tgacttgcaa acctaagcta gaagcttggg atctacagta 1140 aggaggaagg agaattaaag tagagaaaga aaatgtataa ggagaaaggg aaaagaagga 1200 acaaagaggg aaaagaagaa aaaacaagga tgcctgctaa tggcaggaag tggtaaagtg 1260 cctataacta caacttacaa gccacccact aattctaatg ccattcattt gcctactcca 1320 ataataagaa aagctggctt tactggaata tagaatctag agcaacatta cccgcctcat 1380 gttagtgagt aactagtatt ctaaagttgt ttgccataca tatcaagttc ttctaacctt 1440 tgaagcaaac caaaacactt caaaactcag ggctcccagg gctgctgctc cagattccca 1500 gcattcagca tgcttcatta tgtggagaaa gacatttcaa gacaagctgt atctatacac 1560 cttcagaagg aacaaagctc taagaaggtg ggattatgtt aacacatagt acatggttta 1620 gcgtttctcc acatttcaaa ctcaaaatag ctcaataata tgctgctaca tgagcattga 1680 ttctgaatgt tcataatata aacttcaatt tgaagcaaca atgttacaca gttcagctgt 1740 tattaccaac ctactctgta agttaaaata caaataaaat attaatttta ttgagtaact 1800 aaaaataagt tcccactgac ttaaaatcgt caaatggcta actctctctc aactaagaga 1860 gcaacacaga tggaagcaga gaggacaact gaatataaaa taaaatttgt caatctactc 1920 tataatctgc acttttaaaa tccccttttg catatatgta tgtataggat cacagttgcc 1980 caccaacatt atgtctgtca gccctgcaga taacaattta ctgtaacgtt aacaatttat 2040 gcaatactta gtatgtttta tcttatgtgt acagatttac agtttggaat aaaggcagaa 2100 tgattaaaaa ctattgggtt aaagtcttag tatggtactt acctgcaagg ctgaattaat 2160 tttttggaag gctattcaat agctgaacta aaatgcttgt ttaacaaatc aaaagaggaa 2220 taagactact ttaaaacata ttgaaaaagg taaatcccaa tttgaagatc aatcatataa 2280 cgaaaaaagt atgaagtatc ctttgctctt gcttagaaac acatagcaga acagtagaaa 2340 ctagaactca tgaatataag gtaaacccta ttttcccact gatttccatt atacaattgg 2400 agtgaaaata ccactcaaac aaaaataaac aaaaaatctt agcaggtaat tctgtgtaga 2460 acagccatgt gggaattgtc tatattacag ctgcagggaa tctcatgtaa gctaggagtc 2520 catcttccta tgttgcactc tgcagtgact tctgactccc agtagctcct ctattgccta 2580 ctccatatta cgctaatttt tgccccctga ctgctatgct tcctgggact cttattaaat 2640 t 2641 34 434 DNA Homo sapien 34 atttccttat acacacaccg aatcagaata tactttcagt tctacaattt gacaatacac 60 atagctgatt tatagcaagt gtgccatgaa ctgagggttt gtttagtttg tttttgcagg 120 gctgccaata tgctgtcttc acgggacggt aaagaaagta tcacttgggc cgcatctaat 180 atgaaatact gaaggtgggt gtagagaggg tgctagggct ttgaacagcg gcacttcctt 240 tctgagagag agaaaacatc atgctccccc cgcgccgaac tcattttaca ggttgattgg 300 gtgaacaatt cttggcaggc cctgagctag tctgggtatc ctgagtcaag agagaggccc 360 tgcctctgag gtaaagtgtc tctcatctgc ctaagtttgc ttagaaactt tggcttatga 420 aagattaacc taag 434 35 197 DNA Homo sapien 35 tctgagacaa tagggcatgg gtcctctaat tcatctcgag cggcgcatgt gatggatagc 60 ggcgcccggg cagggaaacc cctactggac cctgtgtgtc tgccagcctg gagcctttgt 120 ctccagccct gcctttattc ctccttgcct ccacaccagc ctccccttgc ttctccttac 180 agactatcca agaagtg 197 36 3414 DNA Homo sapien 36 atgggggatt tcgcagcccc cgctgctgcc gcgaatggca gtagtatttg catcaacagt 60 agcctgaaca gcagcctcgg cggggccggg atcggtgtga ataatactcc caatagtact 120 cccgctgctc cgagtagcaa tcacccggca gccggtggat gcggcggctc cgggggcccc 180 ggcggcggtt cggcggccgt tcccaagcac agcaccgtgg tggagcggct ccgccagcgc 240 atcgagggct gccgtcggca ccacgtcaac tgcgagaaca ggtaccagca ggctcaggtg 300 gagcagctgg agctggagcg ccgggacacc gtgagcctct accagcggac cctggagcag 360 agggccaaga aatcgggcgc cggcaccggc aaacagcagc acccgagcaa accccagcaa 420 gatgcggagg ctgcctcggc ggagcagagg aaccacacgc tgatcatgct acaagagact 480 gtgaaaagga agttggaagg agctcgatca ccacttaatg gagaccagca gaatggtgct 540 tgtgatggga atttttctcc gactagcaaa cgaattcgaa aggacatttc tgcggggatg 600 gaagccatca acaatttgcc cagtaacatg ccactgcctt cagcttctcc tcttcaccaa 660 cttgacctga aaccttcttt gcccttgcag aacagtggaa ctcacactcc tgggcttcta 720 gaagatctaa gtaagaatgg taggctccct gagattaaac ttcctgtcaa cggttgcagt 780 gacctggagg atagcttcac catcttgcag agcaaagacc tcaaacaaga acctctcgat 840 gaccctactt gcatagacac atcagaaaca tctctttcaa atcagaacaa gctgttctca 900 gacattaatc tgaatgatca ggagtggcaa gaattaatag atgaattggc caacacggtt 960 cctgaggatg acatacagga cctgttcaac gaagactttg aagagaagaa ggagccagaa 1020 ttctcgcagc cagcaactga gacccctctc tcccaggaga gtgcgagcgt gaagagcgac 1080 ccctctcact ctcccttcgc acatgtctcc atgggatctc cccaggcgag gccttcttct 1140 tctggtcctc ccttttctac tgtctccacg gccactagtt taccttctgt tgccagcact 1200 cccgcagctc caaaccctgc aagctcacca gcaaactgtg ctgtccagtc ccctcaaact 1260 ccaaaccaag cccacactcc aggccaagct ccacctcggc ctggaaatgg ttatctcctg 1320 aatccggcag cagtgacagt ggccggttca gcgtcagggc ctgtggctgt gcccagctct 1380 gacatgtctc cagcagaaca gctcaaacag atggctgcac agcagcaaca aagggccaaa 1440 ctcatgcagc agaagcagca acagcaacag cagcagcagc agcagcagca gcagcagcag 1500 cagcaacagc agcagcagca gcagcaacag cactcaaatc agacttcaaa ttggtctccc 1560 ttaggacctc cctctagtcc atatggagca gcttttactg cagaaaaacc aaatagccca 1620 atgatgtacc cccaagcctt taacaaccaa aaccctatag tgcctccaat ggcaaacaac 1680 ctgcagaaga caacaatgaa taactacctc cctcagaatc acatgaatat gatcaatcag 1740 cagccaaata acttgggtac aaactcctta aacaaacagc acaatattct gacttatggc 1800 aacactaaac ccctgaccca cttcaatgca gacctgagtc agaggatgac accaccagtg 1860 gccaacccca acaaaaaccc cttgatgccg tatatccagc agcagcaaca gcagcagcaa 1920 cagcaacagc agcagcagca gcagcagcag ccgccacctc cacagctcca ggcccccagg 1980 gcacacctga gcgaagacca gaaacgcctg cttctcatga agcagaaagg agtgatgaat 2040 cagcccatgg cttacgctgc acttccatcc cacggtcagg agcagcatcc agttggactt 2100 ccccgaacca caggccccat gcagtcctcc gtgcccccag gctcaggtgg catggtctca 2160 ggagccagtc ccgcaggccc cggcttcctg ggcagccagc cccaagcagc catcatgaag 2220 cagatgctca ttgatcagcg ggcccagttg atagagcagc agaagcaaca gttcctgcgg 2280 gagcaaaggc agcagcagca gcagcagcag cagcagattt tggcggaaca gcagttgcag 2340 caatcacatc taccccggca gcacctccag ccacagcgga atccataccc agtgcagcag 2400 gtcaatcagt ttcaaggttc tccccaggat atagcagccg taagaagcca agcagccctc 2460 cagagcatgc gaacgtcacg gctgatggca cagaacgcag gcatgatggg aataggaccc 2520 tcccagaacc ctgggacgat ggccaccgca gctgcgcagt cggagatggg actggcccct 2580 tatagcacca cgcctaccag ccaaccagga atgtacaata tgagcacagg catgacccaa 2640 atgttgcagc atccaaacca aagtggcatg agcatcacac ataaccaagc ccagggaccg 2700 aggcaacctg cctctgggca gggggttgga atggtgagtg gctttggtca gagcatgctg 2760 gtgaactcag ccattaccca gcaacatcca cagatgaaag ggccagtagg ccaggccttg 2820 cctaggcccc aagcccctcc aaggctgcag agccttatgg gaacagtcca gcaaggagca 2880 caaagctggc aacagaggag cttgcagggc atgcctggga ggactagtgg agaattggga 2940 ccattcaaca atggcgccag ctaccctctt caagctgggc agccgagact gaccaagcag 3000 cacttcccac agggactgag ccagtcagtc gtggatgcta acacgggcac agtgaggacc 3060 ctcaacccag ctgccatggg tcggcagatg atgccatcgc tcccggggca gcaaggcacc 3120 agccaggcga ggccaatggt catgtctggc ctgagccagg gagtcccagg catgccagcg 3180 ttcagccagc ccccagcaca gcagcagata cccagtggca gctttgctcc aagcagccag 3240 agccaagcct atgagcggaa tgcccctcag gacgtgtcat acaattacag tggcgacgga 3300 gctgggggtt ccttccctgg cctcccggac ggtgcagacc ttgtggactc catcatcaaa 3360 ggcgggccag gggacgagtg gatgcaggag cttgatgaat tgtttggtaa cccc 3414 37 678 DNA Homo sapien misc_feature (310)..(611) a, c, g, or t 37 tcataatgct gtcgagcggc ccgcagtgtt gatggatcgg ccgccgggca ggtacctgct 60 gtgtggcagg ctctgggctg ggggctttat tcagcttcct cagcctgctt cgacttcccg 120 attagagagc taatgtgaat caccaaccct gtgatgcctc ttgagatgag agttcagatt 180 tcccaagaag atctaagcag ttggtccaaa ttgtagttca ctagcaaatg acccagtgct 240 gtccctgtgg tgtgtttatg acatgatgga agatgctgcc ttcaaaagtg tccacttgta 300 agaagatgtn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 360 nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 420 nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 480 nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 540 nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 600 nnnnnnnnnn nacacacaaa aaaaaggtgg gggaaccagg gcaagcggtc ccgggggaaa 660 tggtttccgc acattcca 678 38 461 DNA Homo sapien 38 gtgcggccga ggtaccaact gacatttcag tttttctgtt tgaagtccaa tgtattagtg 60 actctgtggc tgctctcttc acctgcccct tgtggcctgt ctacaattct aaatggattt 120 tgaactcaat gtcgtcgctt ctggtttcct gcatatacca atagcattac ctatgacttt 180 ttttttcctg agctattttc actgagctga gctaatgaac taaaactgag ttatgtttaa 240 tatttgtatc aaatacataa aaggaatact gctttttcct tttgtggctc aaaggtagct 300 gcattttaaa atatttgtga aaataaaaac ttttgttatt agaaaaaaaa aaaaaaaaaa 360 aaaaaaaaaa ggcttggggg aaacccgggg ccaaaagcgg tgtcccgggg gggaattggt 420 ttctccggtc caaattcccc aaaaaaatcg agaagaaaag t 461 39 633 DNA Homo sapien 39 caacaccatc tttttttttt tttttttttt ttgagacaga ttcttactct gcactccagc 60 ctggtgacag agcgagattc catctcaaaa aaaaaaaaac agtatgcacg tacaaatttc 120 ttaacctgtt atcaatgtct gagctacata attatctttc tagttggagt ttgttttagg 180 tgtgtaccaa ctgacatttc agtttttctg tttgaagtcc aatgtattag tgactctgtg 240 gctgctctct tcacctgccc cttgtggcct gtctacaatt ctaaatggat tttgaactca 300 atgtcgtcgc ttctggtttc ctgcatatac caatagcatt acctatgact ttttttttcc 360 tgagctattt tcactgagct gagctaatga actaaaactg agttatgttt aatatttgta 420 tcaaatacat aaaaggaata ctgctttttc cttttgtggc tcaaaggtag ctgcatttta 480 aaatatttgt gaaaataaaa acttttgtta ttagaaaaaa aaaaaaaaaa aaaaaaaaaa 540 aaggcttggg ggaaacccgg ggccaaaagc ggtgtcccgg gggggaattg gtttctccgg 600 tccaaattcc ccaaaaaaat cgagaagaaa agt 633 40 536 DNA Homo sapien 40 ggggccgccc gggcaggtac ttgacagtgt tatctgtcac ttatttaaaa aaaaaacaca 60 aaaggaatgc tccacatttg acgtgtagtg ctataaaaca cagaatattt cattgtcttc 120 attaggtgaa atcgcaaaaa atatttcttt agaaacataa gcagaatctt aaagtatatt 180 ttcatataac ataatttgat attctgtatt actttcactg ttaaattctc agagtattat 240 ttggaacggc atgaaaaatt aaaatttcga tcatgtttta gagacagtgg agtgtaaatc 300 tgtggctaat tctgttggtc gtttgtatta taaatgtaaa atagtattcc agctattgtg 360 caatatgtaa atagtgtaaa taaacacaag taataaatga agtgtttgtt ataaaaaaaa 420 aaaaaaaaaa aaaaaaaaaa aaaaaaaagg gtggggggaa cccggggcca aaaggggttc 480 cgggggggaa attggtttcc gggccaaaat ttccaacaat ttgggagaaa aaaggt 536 41 1206 DNA Homo sapien 41 gtactctccc aaatgcagcc taatcttagt aaccttgaag tttatcattc tttaaaacta 60 aatagaatac caatggttta gatattccaa caaagaatgc tagaaacaaa tgtctaatct 120 cgattattag ctttaccaac cctgtgaaca ctgaggttgc agaactgcca ggttaatccc 180 tgtggcctag actactgagg attctgatag cacatgtaag actaagcact cttcaagctg 240 taataaagca tccacatgta tctgtgatga ttttcattgc tttagcattg cagccatgta 300 acaactgcag aaagaaggta tttttaaaaa tacaatagac tacacttttt ggatcacaga 360 gaaatacaga tgcactctga gactgcctat gtttataaac atgttgtgtc ccctaactga 420 agtgacaggt cttctggaat tgacattaag aagtgtggat agtcatatca cacgcaatgt 480 atttgttttc agcagtgagc agaccgtaca ggagcagcac accaggagcc atgagaagtg 540 ccttggaaac caacagggaa acagaactat ctttatacac atcccctcat ggacaagaga 600 tttatttttg cagacagact cttccataag tcctttgagt tttgtatgtt gttgacagtt 660 tgcagatata tattcgataa atcagtgtac ttgacagtgt tatctgtcac ttatttaaaa 720 aaaaaacaca aaaggaatgc tccacatttg acgtgtagtg ctataaaaca cagaatattt 780 cattgtcttc attaggtgaa atcgcaaaaa atatttcttt agaaacataa gcagaatctt 840 aaagtatatt ttcatataac ataatttgat attctgtatt actttcactg ttaaattctc 900 agagtattat ttggaacggc atgaaaaatt aaaatttcga tcatgtttta gagacagtgg 960 agtgtaaatc tgtggctaat tctgttggtc gtttgtatta taaatgtaaa atagtattcc 1020 agctattgtg caatatgtaa atagtgtaaa taaacacaag taataaatga agtgtttgtt 1080 ataaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaagg gtggggggaa cccggggcca 1140 aaaggggttc cgggggggaa attggtttcc gggccaaaat ttccaacaat ttgggagaaa 1200 aaaggt 1206 42 209 DNA Homo sapien 42 ccgggcaggt ggaacttagt gggcagcatt acgggcagcg ctaaggaacc atttaaagta 60 agacaagtcc acacagctgt ggtgcttttc tacgagtctt gttccaactg ctgcataaca 120 atagaatgtt ggaagcagga attagtttta aagtaagact tcagaagtgg aaacaaattt 180 gatatttatt tttataatga tataatagc 209 43 706 DNA Homo sapien 43 gaaccctcca aaacatctga aaagcaaatt tggggggatg aggaagtgag atgatgactt 60 gattctcctt ctaggaagaa tagaggaacc cttctggcaa aatttcaagc atctacaaga 120 ggaggttttc cagaaaataa agacactggc tcagctctca aaggatgttc aggatgtcat 180 gttctacagt atcctggcca tgctcagaga cagaggggct ctacaggacc tgatgaacat 240 gctggaattg gacagctcag gtcatttgga tggccctggt ggtgccatcc taaagaaact 300 tcaacaggat tcaaaccatg catggtttaa cccaaaggac cccattcttt atctccttga 360 agccataatg gtgctgagtg acttccaaca cgatttgctg gcctgttcca tggagaagag 420 gatcctgctt cagcaacagg agctggtaag gagcatcctg gagccaaact tcagataccc 480 ctggagcatt cccttcaccc tcaaacctga gctcctcgcc ccactccaga gtgagggttt 540 ggcatcacct atggctgctg gaggagtgtg gccttaggac ggagctggat aaccccaggt 600 caacctggga tgtagaagca aagatgccct gtctgtcctc tatgggactc tctcgttgct 660 gagcagtggg tgaaggctaa gcctccctga tgggagcagt cagaaa 706 44 1298 DNA Homo sapien 44 atatgaagtt aaaaccagag ctatttctga cacagcaatt tttgagcggg catttgccaa 60 aatacgaaca agttcacatc ctcccagtag gtgagtgtga gtttgctgga ggtgggggtg 120 gggatcccat cctgcacaca tggggtaagt agggcagatt gcccctgcct cgcctttgcc 180 accaccgccc tagggcctgg cgtttggtca tgtggaatgg gaagggtcca gaaagctgag 240 aacatggagg atgaatggga atgggggcag gaagaagttg agtaagaggg aggaggtggt 300 aggagagcag aaccctccaa aacatctgaa aagcaaattt ggggggatga ggaagtgaga 360 tgatgacttg attctccttc taggaagaat agaggaaccc ttctggcaaa atttcaagca 420 tctacaagag gaggttttcc agaaaataaa gacactggct cagctctcaa aggatgttca 480 ggatgtcatg ttctacagta tcctggccat gctcagagac agaggggctc tacaggacct 540 gatgaacatg ctggaattgg acagctcagg tcatttggat ggccctggtg gtgccatcct 600 aaagaaactt caacaggatt caaaccatgc atggtttaac ccaaaggacc ccattcttta 660 tctccttgaa gccataatgg tgctgagtga cttccaacac gatttgctgg cctgttccat 720 ggagaagagg atcctgcttc agcaacagga gctggtaagg agcatcctgg agccaaactt 780 cagatacccc tggagcattc ccttcaccct caaacctgag ctcctcgccc cactccagag 840 tgagggtttg gccatcacct atggcctgct ggaggagtgt ggccttagga cggagctgga 900 taaccccagg tcaacctggg atgtagaagc aaagatgccc ctgtctgccc tctatgggac 960 tctctcattg ctgcagcagc tggctgaggc ctaagccctc cctgatgggc agtcagtcca 1020 gagatgctgg ccctcgccca gtctatgctg tgagtgtcct tatgggtgca agagataggg 1080 ctgtgcctct ctgcgtttcc aggtggagta gagacagtaa tgggtagaga ctttaggaaa 1140 tgttttgggg tggtggaata ctctatatat tgacaagagt ttatatattg acaagagttt 1200 atatatttgt caaaactcct caaatagtat gttaaagacg taagcgtttc actatgtata 1260 aattttactt caaaataata aaaacaaata ctgactct 1298 45 531 DNA Homo sapien 45 acaacattca aacaaccagt ggtgaggttg taaatcaaat gagagaggag gaactgatcc 60 gggtagcagg aacacatttc caagtaaaat ttgcaacaga gcatgttgag atcatggttt 120 taatttatga atggcattat tatctttaaa ctattatttt ccaagctcat atatggcctt 180 tttgaaggtt ttccgaatgt tacatttgat tttaagatct aatccaaaat gaaatataga 240 atgtgcttag ttttctataa aaatgccaat gactatctct taaattagtc aaggaaagac 300 aaattaccaa aattcaaact tatttgaatt atttttaagt gattccaggc aataaataca 360 tagaacccat ggaaagtttt agcttcaaat cacaaaattg caaaaaaaaa aaatggtaaa 420 tggctaaaca taaggggggt tatggaaaat attgggtcac cttaattata ggtttaaatg 480 ccacaaacaa tataataata gttttaactt acttttttcg attactaagc a 531 46 469 DNA Homo sapien 46 taacgccatc agctcgctgc ttaaagccgt gtttgcgtct cattttctca aagaaatctg 60 ctttagtttg agattacagt ttatcaaatg ttaaggcttt gaccccaaaa tctggtccca 120 gaaagacagg aaggccagct aagaggaggt tttcagagtg cgtagaaagg ctgctctgtg 180 cttcggcatt tgttctggaa gtgcttcttc ggttggcaaa gattcctagc aaaacctttg 240 actggaggct ttacagggcc atacacccaa tatcactaat gacagtgttg taaaatagct 300 tttgtgcacc atgcttagga ttcaaggagg ataaagtata tctttctaaa gttatacttt 360 agaaactgtc attccatgtt gaaatgataa acattccatg tttatctttt gtgtaagaag 420 taaaaaagca aaaattcatt gcatcaaagt aggtcaggca ctgctaaag 469 47 483 DNA Homo sapien 47 aaaccgagtt ctggagaacg ccatcagctc gctgcttaaa gccgtgtttg ctctcatttt 60 ctcaaagaaa tctgttttag tttgagatta cagtttatca aatgttaagg ctttgacccc 120 aaaatctggt cccagaaaga caggaaggcc agctaagagg aggttttcag agtgcataga 180 aaggctgctc tgtgcttcgg catttgttct ggaagtgctt cttcggttgg caaagattcc 240 tagcaaaacc tttgactgga ggctttacag ggccatacac ccaatatcac taatgacagt 300 gttgtaaaat agcttttgtg caccatgctt aggattcaag gaggataaag tatatctttc 360 taaagttata ctttagaaac tgtcattcca tgttgaaatg ataaacattc catgtttatc 420 ttttgtgtaa gaagtaaaaa agcaaaaatt cattgcatca aagtaggtca ggcactgcta 480 aag 483 48 600 DNA Homo sapien 48 tccatttctc atggcttgct catcttccgg cttcaggctc tgacttcatc tcaggatggg 60 atcggtgtgt gtctgttttc atagatccac tacatcagaa gtatctttac atctctgtat 120 ctttacatcc caaggtcaag gccctggcaa cctcagaggt tcccatagct tcagtcttcc 180 ccaaaccatg ccacttcctc ccatttcttt gggtcaggaa tctggctttt gttttccata 240 tttctttttc ccaagacatt gggaggcatc tggtgaacaa caccaataaa acagttctct 300 ccccaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaac aaaaaacgaa 360 gaacaaagaa cagagaaaaa aaaaaacaag aaacaccaaa aaacaaaaaa gaaaacgcgg 420 ccgccagcgc acgcgcgagg gcgccggagc acaccctgtg gccagcccgc gagcgagaag 480 ggagcgggcg gggcgggcgg gaccggagac ccaaggaggg cgcagggagc aacgaacggg 540 agccggagga gcgcgacact gcacgcagga gagcagacgg gaggggagac agcgcgggga 600 49 1098 DNA Homo sapien 49 aacctcttca acaataaatt gctctttggg gacattttat gcacagaact gtgcaccctc 60 ctcagaacag caggtcttta atggcccatg tgatgagaag ggccccatca aggcagcagg 120 aatgggccac tctcccacac cccatgggcc aggccactgc cactcctgct gccctgcatc 180 cccaggttta tggctgcatg gtagaagtca cttctgtaag aaattcacct ttctaaaata 240 aagtatgctc ttttttctga gacatctata gaataacttg tggcagagtg ttttaaaaac 300 tgatttggat tttttttatc ctttaaccgt gtgaaaggat ggaagggatt ttaggtggaa 360 gagaagttaa gaacagaaag atagagcagg tttttagagt gggagaatta atcccaaaga 420 aaaagagggc atggaaacaa atgtggatgc catgggctct gtgccagact tgccagtgct 480 gactggaaca ggccgggctc ctcactcagc ggctcctgcc tcagctgtgg ttcccgcagc 540 ctctgggtct cacggaaccc ttccttggga gttccatttc tcatggcttt gctcatcttc 600 cggcttcagg ctctgacttc atctcaggat gggatcggtg tgtgtctgtt ttcatagatc 660 cactacatca gaagtatctt tacatctctg tatctttaca tcccaaggtc aaggccctgg 720 caacctcaga ggttcccata gcttcagtct tccccaaacc atgccacttc ctcccatttc 780 tttgggtcag gaatctggct tttgttttcc atatttcttt ttcccaagac attgggaggc 840 atctggtgaa caacaccaat aaaacagttc tctccccacg gtcatccagg tcacttctct 900 aactcattcc tgcacacaca gcacacgtgg aatttgcctg tttagtctat gttcttgact 960 tgatcacaga cgcctgtaca ataaagcccc ttttcaacaa ggtgctgcag aatgataatg 1020 ctttccccaa aatctgaaac tgatttgtat cattgaagtt tttttctgta ttaaaaataa 1080 agcaaaatta aaaataaa 1098 50 540 DNA Homo sapien 50 ggtcgcggcc gaggtactcc cgcctcctgg agcggccgac cccacatgga ttctcaacag 60 gtggccggca catcttctga gcctcgctct ctcatctgaa agtggagtgt aagtccaaga 120 agattcattt agacaaagaa ggtggaaaaa aaggactttc tgggccagca agtcggatga 180 ccaccctcca aggggcagag gagggcccat tttgtgaaga agaaatcaac tacccggaaa 240 acgccacagg aggacatgtt tctgcagatg tagttgccct agaaacagaa gagtatgggg 300 gtgtgaatgt cttctctttt gggggcaaac actatgtcct tttctttttc tagatacagt 360 taattcctgg aaattttagc gagtttgttc ttgtggatat tttgaacaat aaagagtgaa 420 aatcaaaaaa aaaaaaaaaa aaaaaaaaaa accctgggcg gtacccatgg cgcaaagcct 480 ggtcccctgg ggggacactg ggttacccgg cccccaattc cccacaattg cggagcaacg 540 51 1028 DNA Homo sapien 51 cggccgcggc atgaaaggcg gcgaggagag gcagcactgc tgctcttgac ttctgagcag 60 ggcttagaga gcctgccccg gcttaagccg agctgctggt gctgaccctg agcgccgagt 120 ccgcgagctc tgagtccgga gcctcccagc cgtggagccg tgggatgagg ggggcgttgg 180 gggacagggc aaagtcgatc ttggttgtac agccgcccga tcctagcgcg gagctgcgag 240 cctgaccggc cgcgtctggc atggtcagag aaagaatttt cttttcccaa ctccggcttt 300 tggttttgtg tgtccacctt gcgcaactcc ggagccagcc gaccccacat ggattctcaa 360 caggtggccg gcacatcttc tgagcctcgc tctctcatct gaaagtggag tgtaagtcca 420 agaagattca tttagacaaa gaaggtggaa aaaaaggact ttctgggcca gcaagtcgga 480 tgaccaccct ccaaggggca gaggagggcc cattttgtga agaagaaatc aactacccgg 540 aaaacgccac aggaggacat gtttctgcag atgtagttgc cctagaaaca gaagagtatg 600 ggggtgtgaa tgtcttctct tttgggggca aacactatgt ccttttcttt ttctagatac 660 agttaattcc tggaaatttt agcgagtttg ttcttgtgga tattttgaac aataaagagt 720 gaaaatcact ttggagtcac ttaatcttcg ttagaagggc agtttcttcc agggccattt 780 tctttcacca gatttgtttt tcctcgttcc caaatgaggt agttttaaaa atcaaagtcc 840 acttgctaac tcacctggga aagagactgc gacagaagga agagaagtaa atagacatca 900 ctctcaaact aaaagtgtaa ctttcattcc tggcagctga gattcagaac acaaagaaac 960 aaactcgttt acctttgagt atttcccccg tatgggtaat ttatctagag ctttcccaac 1020 aattaatc 1028 52 541 DNA Homo sapien 52 acagattggt aaggtgacat tgtatcacaa agctagtctt tgagtccaaa gttttgtggt 60 tttatgttat gatatacttt tatcatggaa ttgtcttatt aaatgttttg ccagtggttc 120 ttaaagtgtg tttctgacac cagtagcatt gacttcactt agaaacctgt tagaaataca 180 aattatttgg ccccacccaa cacttgagtc acaaactttg cagatggggc tcaatctgtt 240 ttaacaagcg cttcatgtaa ttttgatgca ggcctaagtt tttgagccgc tgcagtatgc 300 atttctattt ttaagcaaag atcttggtct ttctttttgg acattgtaga aataacatga 360 acttgtcttt tgtttgtttt ggttttgttt tgttttaagc tcctgatctt tgttggttat 420 gttgcaaaag attgtatcag gagaagcctc agcatggaca ttggcatcct gacataaccc 480 ccattaattt agtattcttt ctgaaactca aatggattct caagtccaag agactatgga 540 a 541 53 261 DNA Homo sapien 53 atgccatcag tggcacaggg ccctgtgccc tggcatctgg gttcacgctc tgctgttgct 60 gtcttcgaat tcctagtgat gtttgaacaa aggccctatg tttgcatttt gcactgggcc 120 ccacaaatca catggcccat cctgagaaga ggagtctcac acctccagtc tcctaaatca 180 cctctggaag tttttctcaa cgaaagaact gaagctttcc tcaaaagttc cgtaggggag 240 acagttcatc accataccca a 261 54 325 DNA Homo sapien 54 gctctgtttt gtgttttgtt tggattgtgc tggttgtgtt ttgtgtttgt ggaaggtgtg 60 tgtgtgggtt tggcgagtac atgtcgcccg ggaccgctat ggctctgggt gcgcccacgc 120 tttttttttt tttttttttt tttttttttt ataatcaacc tataagggat ttatcaataa 180 ataaaccctt atttattata aggaattggc ttacacaata atggaggccg agaaggcccc 240 aagtctgctg tccgaaggtc tgagaaccag gagcactgat ggtgtcagtc ccagttcaag 300 ggcaggagaa gatgggtgtc ccagc 325 55 2461 DNA Homo sapien misc_feature (356)..(393) a, c, g or t 55 gcctgaatag agctgtgcag cccaaggggt ggactgagcc agcagtggat atgcaccact 60 gagatctctt gctgtggaac gtaattgact gggggggtcc ccgctactgc tctctgaatc 120 cattgataca gtcatgccaa ggctacattt cccatgggtt gtttccataa gaataacaat 180 aactgaatga agaaggtata ctaataatgc aggcctattc ctgtgaggta gggggctcct 240 ccaatgggcg actttggttt gagtgttctt catcagctga ccttaaactt tattggaatt 300 gtgctacagc ctaagctttc tgctactcaa cccgcctttc ttccctctct ccttcnnnnn 360 nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnaaaccta tggctctatc aatcaattaa 420 taaggattta taatcaacct ataaggattt atcaataaat aaacccttat ttattataag 480 gaattggctt acacaataat ggaggccgag aaggccccaa gtctgctgtc cgaaggtctg 540 agaaccagga gcactgatgg tgtcagtccc agttcaaggg caggagaaga tgggtgtccc 600 agcgccacag tcaggcagaa aattcaagct tcctccacct attttatttg ggtccttaga 660 agactggatc aagcccatcc acactgggga ctgcaatctg ctttattcag tccatcaatt 720 caaatgcgaa tttcctccag aaaaagcttc atgaacacaa ccagaaataa tgttcgatca 780 tatatggggc atcctgtggc ccagcgaagt tgacatgcat aaaattaacc atcacacctc 840 catggaggcc agaaatttta tgtattctga ggactctgtc tctctggctt cctctccatt 900 tcaaccctca ggcattcttt ttttccccaa ataaatgtct tgtaaatcta tttttttttt 960 acatgtgttt tttttggagt actggaacta ataaatttgg actttgttct gcaggtagtt 1020 tagttactta cagatcagct ttatactatt gaggcttgtt tttaagcttt ttgtgggggt 1080 gaggagcaag tgtagtgtag tttttagtca ggatagttta gccctacgta tgtaacacac 1140 aacctttctg ggatctttag cgaatgcctg gttttcagtc aggactctcc actgtggctg 1200 gatggaaatt agatatttcc caatctcacg ctaattttga gaattgttag gcttagtgtt 1260 ccgcaatgta cacaatgggg tctctacata gatttctgga tttttttgtc taccttcctc 1320 cttgttgata ctttgtcctg aaaattcaag ctatctcagt atcaactcca atcttcctct 1380 cctcaactca gcaagactct gatctcctgc gatgggatcc agagtgctca cctcagaaag 1440 gcagggcgat cggaggtctc actttgtttc cctgcctcag cgatcaaatt gtataaactt 1500 tttccctggc ttctggaaac actgatagcc aacctttcgg taaaatttct aacatatgta 1560 cttagagctt taatatgcta agtatttaaa tgctaagtat tttctttaaa attcatttca 1620 aaatattttt gcaattttgc cgtgatttat tttttggctc atgggtcatg aggtgtatgt 1680 tccttaaatt aatgcatttt ggaaattttt tgttaccttt atgtacttga tttctggttt 1740 aattcatact ctatatgatt tcaatctttt gaaatttctt gagacttgat ttgtgatcca 1800 gcctaacatg cgccccagaa cacatggtaa atgttttggg gtatacttta aaagaacatg 1860 tattctgatg tttttgaatg taatatctta tgtcttattc atatttatag taccaataca 1920 cagcacatag tagaaactta acatatattg agttaaataa ttcaaaggtt ttatccgatt 1980 ggtggcaatt caagaccaaa taagagagga tgatgatgac atcactattt ctgttaagac 2040 agggcctcat acaacataca ggaatgtcca gttgtcaagt catgcagttt ctcccctatt 2100 ctaaccaatg ttaatgccaa tactttgtga tgaaaattat cccagtattt ttcctcctat 2160 gtttccacca gttttccctt cattgattgt taagatttat atcactagag ctatttgaca 2220 gtaggaaaca attaccttag gaaaagttgg tgacattggt ctataaaggt cacggagaca 2280 taagaaatgg ttattttttc atttttcacc aaacaattca cgattgtttc taagattaca 2340 aaagattaga cgatagctaa tatttctatg caatggtcaa atttttcaag tagaatcatt 2400 tttaaatttt ccaagttcca atgtcacttt ctccttgaac acgactcaag gtcaaaactt 2460 a 2461 56 643 DNA Homo sapien 56 ccgcccgggc aggtacacat gagtgcgtgt atgcccccag gctgggtcag ctcttctgtg 60 gattgcatgg cgtgtgatta aaagcccatg tgttcccaca catccacatc atgggaaggt 120 taatgtgtgc ctccttggaa ctgggtgttg gtgtccatgg aacttcctct ctgtatctca 180 ggtcagtagg cgcagaaacg cctcatgatg aagattcttg agccccattt ccaagacccc 240 tcacatccaa tcctgtcctg taacatccat caaggatttc cataggggtg actggtgccc 300 acccaagact gcaccagtgc ctgctcattg aggagagtaa ctgctggcca ggcagaaaga 360 atatgggctc tgcaatgaga cagacctgga ggggactctc ccgttgagca ctagcagctg 420 gaggagttgg gagttcatgg ctatcatggt tgtgttcaat cgattgtggg gatgacatgt 480 cattgtgtat ggaaggcggg gctcatggct gattggccaa taaaatggcg gctgccgttg 540 tcattgaaaa aacacaccac accacaacca aaaccgctgg ggcacacccg ggcacaaggc 600 cccccgggga aacgggttcc ccgcccaaat tctccaaatt aga 643 57 1611 DNA Homo sapien 57 ctcctcccga ggaaccagtg gtgacagctg aggccatgtg agtaggatcc tgaatgaggc 60 tttatctctg gctgttcgtc ccatcgtcca ccgtggcacc agctccctca gccagccggg 120 atgggaccag cgactgagag agccagaggc agagaggtga gggtgaccat atcctggact 180 gtgagaggaa tgggactctg ggcctgtagc tgccaagcag gtggcaggtg ctccaggctg 240 tgatctgcac cctctgaccc ctgacattga cctcctaccc tgacccctgc ctgaccaagc 300 catgtctgaa caggaggctc aagccccagg gggccggggg ctgcccccgg acatgctggc 360 agagcaggtg gagctgtggt ggtcccagca gccgcggcgc tcggcgctct gcttcgtcgt 420 ggccgtgggc ctcgtggcag gctgtggcgc gggcggcgtg gcactgctgt caaccaccag 480 cagccgctca ggtgaatggc ggctagcaac gggcactgtg ctctgtttgc tggctctgct 540 ggttctggtg aaacagctga tgagctcggc tgtgcaggac atgaactgca tccgccaggc 600 ccaccatgtg gccctgctgc gcagtggtgg aggggccgac gccctcgtgg tgctgctcag 660 tggcctcgtg ctgctggtca ccggcctgac cctggccggg ctggccgccg cccctgcccc 720 tgctcggccg ctggccgcca tgctgtctgt gggcattgct ctggctgcct tgggctcgct 780 tttgctgctg ggcctgctgc tgtatcaagt gggtgtgagc ggacactgcc cctccatctg 840 tatggccact ccctccaccc acagtggcca tggcggccat ggcagcatct tcagcatctc 900 aggacagttg tctgctggcc ggcgtcacga gaccacatcc agcattgcca gcctcatctg 960 acggagccag agccgtcctt cttctcacag cggcctcagc gtccccagag ccgagccagg 1020 gtgtgagtgc atgtgaacgt tgagtacaca tgagtgcgtg tatgccccca ggctgggtca 1080 gctcttctgt ggattgcatg gcgtgtgatt aaaagcccat gtgttcccac acatccacat 1140 catgggaagg ttaatgtgtg cctccttgga actgggtgtt ggtgtccatg gaacttcctc 1200 tctgtatctc aggtcagtag gcgcagaaac gcctcatgat gaagattctt gagccccatt 1260 tccaagaccc ctcacatcca atcctgtcct gtaacatcca tcaaggattt ccataggggt 1320 gactggtgcc cacccaagac tgcaccagtg cctgctcatt gaggagagta actgctggcc 1380 aggcagaaag aatatgggct ctgcaatgag acagacctgg aggggactct cccgttgagc 1440 actagcagct ggaggagttg ggagttcatg gctatcatgg ttgtgttaat cgattgtggg 1500 gatgaaatgt cattgtgtat ggaaggcggg gctcatggct gattggcaat aaaatggcgg 1560 ctgccgttgt cattgtctcc aaaaaaaaaa aaaaaaaaaa aaaccgcgga c 1611 58 617 DNA Homo sapien 58 actgtgaagt cttcaggctc ttagaaggct ccagcctgag agagcccttt attattgcca 60 ttcctgtcct tcctcaaggc ctggtgacct gtgacctttc gctctgggca gggcccaggt 120 agatgggccg tcatccgggc ctgtaagccg tactatgatt tctgcattga tttacatatt 180 ttttactgtg atcttggttc caaacacaga atcgtcaccc cattctccct tgaatgtgcc 240 ggatccttgt aaattctcat tcacctactt gttcttaggt gtgtatgtgt gtgcgaaact 300 ctatgttcaa gaaagaaatc atacaaagag taacgaacca tggttctgtt ggccattgga 360 cgaaacttgg tttttggact ttcttaccta acattaattt tgctcttgcc tcggtttaca 420 cacacacaca cactacaaca aacacaacac aaacaacgtt ctgggccaac accacgcggc 480 gccagcgccg gctccctggg ttgaaacttg gatctcttcc cgcgccacaa ttctcccaac 540 aactataatg agcacaagga ccacaaccat acacaagaac aacacaaacc agcgacacaa 600 cagagacaac acacaac 617 59 913 DNA Homo sapien 59 caaaaccaca cccatgcaca cacataccct cagcccccac acacaccccg ttgaacccgt 60 gagtctatca gggcatccta aaactccgtg agttgacatt tcagtaattt caggggaagg 120 tgttttccag ggatggggtc tcccaggttc agatagtgcc tttggctgca aatgctcctt 180 tagctaaact tttcctcagg aagaattcat tattctagac attatgtgat atatctgtta 240 ggaataaaag gtgcttaacc ttcctccctg ggatgtggga gaaggtgctg gaggttgtac 300 tgtgaagtct tcaggctctt agaaggctcc agcctgagag agccctttat tattgacatt 360 cctgtccttc ctcaaggcct ggtgacctgt gacctttcgc tctgggcagg gcccaggtag 420 atgggccgtc atccgggcct gtaagccgta cttgatttct gcattgattt acatattttt 480 tactgtgatc ttggttccaa acacagaatc gtcaccccat tctcccttga atgtgccgga 540 tccttgtaaa ttctcattta cctacttgtt cttagtgtgt atgtgtgtgc gaaactctat 600 gttcaagaaa gaaatcatac aaagagtaac gaaccatggt tctgttggcc attggacgaa 660 acttggtttt tggactttct tacctaacat taattttgct cttgcctcgg tttacacaca 720 cacacacact acaacaaaca caacacaaac aacgttctgg gccaacacca cgcggcgcca 780 gcgccggctc cctgggttga aacttggatc tcttcccgcg ccacaattct cccaacaact 840 ataatgagca caaggaccac aaccatacac aagaacaaca caaaccagcg acacaacaga 900 gacaacacac aac 913 60 554 DNA Homo sapien misc_feature (304)..(430) a, c, g or t 60 tggaaaataa agtttaaaac cagattgccc agagcaagac tctaatgttc ccaacggtga 60 tgacatctag ggcagaatgc tgccattttg aggggcaggg ggtcagctga tttctcatca 120 agataataat gtatggtttt tacactaagc aactgataaa tggacaattt atcactggac 180 aatctccctc tgcttcttta atggggccag ctttgcagcc ctgcagcctg ggtagtcgca 240 cacatttcca tgcatccaag gcccccgtgc ttgggagaat gatctgctag tgccatttta 300 aatnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 360 nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 420 nnnnnnnnnn tcactgtgtc cggcataaag tagaacattc ttacaagaaa taaatatttc 480 gtagtcatgg agaagaacgc gaaaaaaaaa aaaacaaaaa aaaggctggg ggtaaccagg 540 gcccaagcgg ttcc 554 61 1401 DNA Homo sapien misc_feature (803)..(929) a, c, g or t 61 aattattttg ggtctctgtt caaatgagtt tggagaatgc ttgacttgtt ggtctgtgtg 60 aatgtgtata tatatatata cctgaataca ggaacatcgg agacctattc actcccacac 120 actctgctat agtttgcgtg cttttgtgga cacccctcat gaacaggctg gcgctctagg 180 acgctctgtg ttcactgatg atgaagaaac ctagaactcc aagcctgttt gtaaacacac 240 taaacacagt ggcctagata gaaactgtat cgtagtttaa aatctgcctc gcgggatgtt 300 actaaactcg ctaatagttt aaaggttact tacaatagag caagttggac aattttgtgg 360 tgttggggaa atgttagggc aaggcctaga ggttcatttt gaatcttggt ttgtgacttt 420 agggtagtta gaaactttct acttaatgta cctttaaaat agtccatttt ctatgttttg 480 tataatctga aactgtacat ggaaaataaa gtttaaaacc agattgccca gagcaagact 540 ctaatgttcc caacggtgat gacatctagg gcagaatgct gccattttga ggggcagggg 600 gtcagctgat ttctcatcaa gataataatg tatggttttt acactaagca actgataaat 660 ggacaattta tcactggaca atctccctct gcttctttaa tggggccagc tttgcagccc 720 tgcagcctgg gtagtcgcac acatttccat gcatccaagg cccccatgct tgggagaatg 780 atctgctagt gccattttaa atnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 840 nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn 900 nnnnnnnnnn nnnnnnnnnn nnnnnnnnnt cactgtgtcc ggcataaagt agaacattct 960 tacaagaaat aaatatttcg tagtcatgga gaagaacgct cctaaaatga tgaacgcacg 1020 acggaaaaga gtagggaaca ttttgcttga tgagaaaatc cgccagcaag gatgttgggc 1080 tctaagcaga actgaagctc tggaattaag aacacagcca aggaagagct ctggactctg 1140 agtttaaaga agctgactga cttgtaaggc aattccaggt aagattggtg aatcaagtta 1200 agaatcaaaa gcaactgaga tcaacgtgga ggcctggaag gtaagggcca tattttacct 1260 agatactagc ttagagactt gctacattgg cactgtattt taagtatgtt atttagtagt 1320 attgtgaaat caactggttt caacattgaa aaggataaaa atagcttatg aaaacaaaac 1380 ggtttttttt tttttttaaa a 1401 62 568 DNA Homo sapien 62 agatgctgcc gagcggcgca gtgtgatgga tagtccaaaa aaaaaaagta ttaaaatgtg 60 attgatgtaa tttaccatgt ttactttatg catgcatttt attggggagg ggacgtgtca 120 gaataataca cccaaatcta gtggtctaat ttcatagtgc taatctggtt tatattggca 180 ttaaacgata ctgcgaagga gctagatcat tttacaagag ttgtaggttt gtcttatgtt 240 ggaaaagcag tcctctatta atatcatgtg tgaagagtat ctgttcacaa gatttatgag 300 attatgacgt gtttcagaga atgtctacta gtatatcttt acagtatttg cctgttgaac 360 tccctgcaca aactggaatt actttccaga agacttaggg aatgcaaata tgttactcat 420 aagatgcatt ggagtatggt aaataaaaca aaccattttg gattggttta aattggctcg 480 ttacagttct cttgtgggga gggactttgt cagtcatttt ggcatcttaa gctagactaa 540 actttttgtt gttgttttcc taaaacca 568 63 791 DNA Homo sapien 63 tggtctatgg taatttttta tagcagtccc agccaagaca gtgcgctcat ttactacata 60 ccatttatat tattatatag gctcctttca gaaacccatg ttcaaataag agataagata 120 ctgaaacaca taacaccttc actagttttt agtatacaaa tattgagaaa tagttgttat 180 taactatctc atccaagaaa tgcagattca tgttgtttct aaatttttta tatatattga 240 ccaaaatgaa gaaacttaac accatcctag attttagctg cccaaagaat gaaaagaatg 300 aaaaaaaaat cttgtgaaaa cccacaagtg atatggatct aatttatggt taaatagata 360 tagataacaa acagaatacg cctgtttaaa actgttaaaa tgacattggt tctaattata 420 cttttattta aattgaaaga caaggcattt atatggtatc tctaaccatc acaactttgg 480 tgtgacaaaa agaaattatc accaaaatac acctccttaa gtaagtgtct gatttcacac 540 ttccagaaaa agtgctcttt ctggtcaagg ccagcaagaa ttgagaaaga ttaagaaagt 600 gcttcaaaga tgtttattac aaagttgtca taaaaactgt gaagtagatg tagacatcaa 660 gcataccaaa taaagtaaaa actgtcctcc ggcaaaacaa caacccaaaa aaaaaagcgg 720 gggggggacc ggggccaaaa cgggtcccgg ggggaatggt tccgccaatc accccaacaa 780 aaaaaaaagg a 791 64 1523 DNA Homo sapien 64 gggagatgct gccacctagg ttacttgtag gaccctatac ggcaacctcc tttgccagga 60 actatttata aacatcctgc aggaaaatgc agtgaagtag aagagacagg gatatcccag 120 aaggttatgc aaaacatcaa gagaagatga gaggagtcta tatgtcagaa tacacatttc 180 ccaccttgcc caacagtaga aaaacataag aagagaaaaa cattaaaaaa tgacaaggaa 240 gttaatggaa gtcagcaatg tgatggtgtt tggaggtgga gccttcagaa ggtaattaat 300 gcccttgtaa gaagaggcca gagagcttgc gcaccttctt cctgccatgt gaggagccaa 360 gaagccggct gtctgcaacc tgcaagagga ccctcactag aagctagcca tactggcatc 420 ctcatcttgg ctttccaact tccagaactg tgagaagtat atgttgtggt ttagtcaatg 480 gtctatggta atttttttat agcagtccca gccaagacag tgcctcattt actacatacc 540 atttatatta ttatataggc tcctttcaga aacccatgtt caaataagag ataagatact 600 gaaacacata acaccttcac tagtttttag tatacaaata ttgagaaata gtttgttatt 660 aactatctca tccaagaaat gcagattcat gttgtttcta attttttata tataattgac 720 aaaatgaaga aacttaacac catcctagat tttagctgcc caaagaatga aaagaatgaa 780 aaaaaaatct ttgaaaaccc acaagtgata tggatctaat ttatggttaa atagatatag 840 ataacaaaca gaatacgcct gtttaaaact gttaaaatga cattggttct aattatactt 900 ttatttaaat tgaaagacaa ggcatttata tggtatctct aaccatcaca acttttgtgt 960 gacaaaaaga aattatcacc aaaatacacc tccttaagta agtgtctgat ttcacacttc 1020 cagaaaaagt gctctttctg gtcaagccag caagaattga gaaagattaa gaaagtgctt 1080 caaagatgtt tattaaaaag ttgtcataaa aatgtgaagt agatgtagca tcaagcatac 1140 caaataaagt aaaactgtca tcaagaagat tcaacagcta tgaaaagagt tcttcaaaat 1200 atgatatgtt tttctagatg ataataaaat ttatcaattc caaatgtcca cattagtctt 1260 tcataaagac accaatgagt cacaggaaaa aaattaaaaa taaaaaaacc ctatctcagg 1320 gaatcatgct aacaacctga tgtgttttct tccacatatt tatgtctgct tataagtatt 1380 tacaaacata tattcgcata tatgcatttt gaattttttc tgttgctgca cttaaatttt 1440 tttcataata aaacaagact cctgcaattt gcttttttag gtagactatg tatccctgac 1500 aaccatccag gtcagcttga tga 1523 65 377 DNA Homo sapien 65 ggtcgcggcc gaggtacaaa agtgcaaaca aggttagtga ttaacaactt accatcaata 60 taccacttca acatacttta cattcagcca aatactgaag gtttcaccgt ggaaaaacac 120 ttttatcact tttaaagtaa cttgactatg ttcaccctga gtgctcttgc ctcagtatgg 180 caactgatta tgagttcagg ttaagagcaa caccagggaa tacagaaacc cacgttaagt 240 tggccattct gacatgaatc tatacttgaa aatgaaaaca atcccaaaga aaacctgtat 300 gtcaaaaaca gaactgttcc tgcctttcac cccaaaatat ttaaaactaa atctaagcca 360 cttttaaaat gcatgct 377 66 1703 DNA Homo sapien 66 ccaggctgga gtgcagtggt gtgatctcca ctcactgcaa cctccacctc ccagcttcaa 60 gtgattctcc tgcctcaacc ttccaagtag cttggattac aggcgtgcgc caccacagct 120 ggctaatatt tgtattgtta gtagagacag ggtttcacca gtgttgtcca ggcttgtcga 180 acttctgacc tcacgtgatc cacctgcctc agcctcccaa agtgctagat tataggcgtg 240 aaccactgcg cccggccagc atgcatttta aaagtggctt agatttagtt ttaaatattt 300 tggggtgaaa ggcaggaaca gttctgtttt tgaaatacag gttttctttg ggattgtttt 360 cattttcaag tatagattca tgtcagaatg gccaacttaa cgtgggtttc tgtattccct 420 ggtgttgctc ttaacctgaa ctcataatca gttgccatac tgaggcaaga gcactcaggg 480 tgaacatagt caagttactt taaaagtgat aaaagtgttt ttccatggtg aaaccttcag 540 tatttggctg aatgtaaagt atgttgaagt ggtatattga tggtaagttg ttaatcacta 600 accttgtttg cacttttgta caccactgct tgcactagga tcttggtgtg aattttcaat 660 tgttttacag tgtatacaga ttattaagga taatttatat aaagatgttt ctgtttaact 720 ttgtgtgttt tacaacaaag agctataata gatggttaaa cgtttttgaa ttgtgtttat 780 atgttagttt gattagtatt ttatttttcc cttcctaaca ctcaaattca tggcaggtga 840 aaagataata gaacataatc aaactaacat ataaacacaa ttcaaaaacg tttaaccatc 900 tattatagct ctttgttgta aaacacacag agttaaacag aaacatcttt atataaatta 960 tccttaataa tctagtatac actgtaaaac aattgaaaat tcacaccaag atcctagtgc 1020 aagcagtggt gtacaaaagt gcaaacaagg ttagtgatta acaacttacc atcaatatac 1080 cacttcaaca tactttacat tcagccaaat actgaaggtt tcaccatgga aaaacacttt 1140 tatcactttt aaagtaactt gactatgttc accctgagtg ctcttgcctc agtatggcaa 1200 ctgattatga gttcaggtta agagcaacac cagggaatac agaaacccac gttaagttgg 1260 ccattctgac atgaatctat acttgaaaat gaaaacaatc ccaaagaaaa cctgtatgtc 1320 aaaaacagaa ctgttcctgc ctttcacccc aaaatattta aaactaaatc taagccactt 1380 ttaaaatgca tgctggccgg gcgcagtggt tcacgcctat aatctagcac tttgggaggc 1440 tgaggcaggt ggatcacgtg aggtcagaag ttcgacaagc ctggacaaca tggtgaaacc 1500 ctgtctctac taacaataca aatattagcc agctgtggtg cgcacgcctg taatccaagc 1560 tacttggaag gttggtgagg cacgagaatc gcttgaacct gggaagcaga ggttgcagtg 1620 agtggagatc acaccactgc actccagcct gggtgacaaa gcaagactcc atctcaaaaa 1680 aaaaaaaaaa aaatgagcgg tcg 1703 67 456 DNA Homo sapien 67 atctctttaa ataattagca agaagggaga caagatgcag gagttcactt ggctctttga 60 aaaggaaaac tttaaagtca gtggttggac tgagtcccat gaagccagat cacttctgac 120 tgcaaggagc ttggaaaagc aagtatctgg atcttttacc agctaaattg ggaggaacta 180 taaaatgaga aaagattgat gaatattaag tagaagagtg agatggtcat ctttgcattt 240 aaaaaagatc atttgctgta gttgtatgga aaatgaattg gagcaggcga tgaggcttcc 300 tctttgaaga tcacaggtga gaagattagg tgctttctca gaagcccagc aacctgatgg 360 gagtgtggag tgagcaagac ccaaatcgga gcttcatccc tgcatggttc attttgctta 420 tttggcaaac ttgccctgca gaatctactc aagctt 456 68 380 DNA Homo sapien 68 ccgcccgggc aggtagaggt tgtagtgagc cgggatcacg ccactgcact ctaggcctgg 60 gcaacagaga gagagactgt ctaaaaaagg aaaagaaaaa aatttatacg ccaaaaaaga 120 tattctgaga taacctgtag ttaccactaa ctttgtgaca aaattataaa aatccacagc 180 catctatgaa tctgtaggca gacctgaagt ttgaacgact ggtgaagaca tctgcatttt 240 ctttatagcc aagttaggat aacaaaaatg caaacaagtc attaatattt actatatgca 300 agatacagaa acgatgaacg gaaggagtaa gaagttatcc ttcgtggaac tatttaaagc 360 aaaaatgcaa aataccaggg 380 69 2177 DNA Homo sapien 69 ttccaacatc tcatttctcc catgaactat ttggaaaaag ctgcaggcgt aatattggat 60 ccctaaatac tttattctcc ttataccatt atcagaccca agtatcatct aatagtccat 120 aatcaaactg cctaaacagt ttctacactg tctttttaac tatttcaaac tatcaaggtc 180 cgcattttct tccttagaac ttttagtctt tttcttcccc aaaatatttg agtccatgcc 240 agttgccttt agttgtaccc aaataatggt ttgtctattt cctaaaagta gtactcttaa 300 atttaaattt agtgttattt ttgttgtcat cgttccttct tcctcatgtg gttgtgcagg 360 cagagcttga gcatccagat ttcaaaatta aaaaataaaa gataatctag tttaatatat 420 agtagttgaa tcaccttaag tctagactgc tgtatgagca cccattatct ttcactatat 480 tccatcatcc ccctccccca tgaactattt ggaaaaagct gcaggcgtaa tattggatcc 540 ctaaatactt tattctcctt ataccattat cagacccaag tatcatctaa tagtccataa 600 tcaaactgcc taagcagttt ctacactgtc tttttaacta tttcaaacta tcaaggttcg 660 cattttcttc cttagaactt ttagtctttt tcttccccaa aatatttgag tccatgccag 720 ttgcctttag ttgtacccaa ataatggttt gtctatttcc taaaagtagt actcttaaat 780 ttaaatttag tgttattttt gttgtcattg ttccttcttc ctcatgtggt tgtgcaggca 840 gagcttgagc atccagattt caaaattaaa aaataaaaga taatctagtt taatatatag 900 tagttgaatc accttaagtc tagactgctg tatgagcacc cattatcttt cactatattc 960 catcatcccc caacatatcc acagtagatg aagggcagtt tgctcaaaca ttgttttgat 1020 cctgtcatgt ctgttcagaa atgcctgtct attcagaaac ccacgtctaa taacaaaatc 1080 ttggactggt tactatcaaa acccaacaac atacagactc ctcagctagg ccctagggat 1140 atttttctac cttgatttcc aaatgttcat tgaaagaatg cttaattcta atttggaaaa 1200 aagtttttgg cttcccactt ctgctttaca cgttcatctt tcttgaaatc aaatccaatc 1260 caatctatat tctaagaacc tgctcaaatc ttggttcttc aaagctttcc ctggtatttt 1320 gcatttttgc tttgaatagt tccacgaagg ataacttctt actccttcct tcatctttct 1380 gtatcttgca tatagtaaat attaatgact tgtttgcatt ttgttatcct aacttggcta 1440 taaagaaaat cagatgtctt caccagtcgt tcaaacttca ggtctgccta cagattcata 1500 gatggctgtg gatttttata attttgtcac aaagttagtg gtaactacag gttatctcag 1560 aatatctttt ttggcgtata aatttttttc ttttcctttt ttagacagtc tctctctctg 1620 tcgcccaggc tagagtgcag tggcgtgatc ccggctcact acaacctctg cctcctgggt 1680 tcaagagatt cttaggcctc agcctcccga gtagctaggg ttacaggcgc gcaccacctc 1740 catgcccagc tcttttgtat ttttaagtag agacagggtt tcaccatgtt ggtcaggctg 1800 gtctcgaact tctgacttca ggcaatccgg ccgcctcggc ctcccaaagt gctgggatta 1860 caggcacaag ccactgcacc cagccttatt accataaatc atcttgatgc tggtacctga 1920 taagattcta tttgcttttc tttattcata gagaccacaa acagatcgca gatccaggtt 1980 tctcaaactg gagcatctgc ttaattttcc cataaaatca gtcttattct ttctgacagc 2040 tctgagactc ctccggccac gactaggtgc tgtcctggag gaaacggtgg aggacggccg 2100 cacaaaaacc aatctacctg atgaaaactc cgttcccttc tcgccagaaa cataaaatgc 2160 gatggagacg ctcgtgc 2177 70 226 DNA Homo sapien 70 tctcatgccc attcaatatg gaatgttctt cgcttgctga atttaagcct gtattttaag 60 gttttgtggt tcctcggcca caatgggtga tgtcactgat agaacgaagc tgagtttcta 120 agggtttggg gctgtgcaag agtaaacact agagcttgag ttgttatcca gctggcaagc 180 acggaagtct ttgaagaatg taatgtaaaa agggaacaag aatgta 226 71 2554 DNA Homo sapien 71 gcgggagagc cctgtcctta aacacattag gacaagtagt taaaacaggg ccaagaagta 60 tggctgtgta gtgatcactg tacaagcaca cctggctgaa taaaccagtg ggggataaaa 120 tccagctcac ctgccgctgg ctatgctttg tgcctcagga caagggtgtg cttccttgct 180 aattgacagg aaccatcttc ctgcccaact gcattcccac tgcgtaggca ccttatctgc 240 ccaatggggc tgtgaaccct aattggaagc tttgcaattc ttaacactat atcttcttga 300 gctgggtttg agtccctatc caatcaagat gaaggcctga gaggactact caagttctaa 360 catgatgtgg gggcaaggca tagtagtcca gatccgggac atgaggcagc ttttggctta 420 gtatgacaat ctaatagttc ctaaaataga attatcccag gatggagctc cgtatgacag 480 aagggctctt cataggtagt tggtaggggg aattgtgtat catgtaagaa gtaggaccag 540 atgtctttaa aaagaccttc caactctaat gctacatgag tctgtctagt tgttatgttc 600 caacagggac agctcttaaa atagtgtggc aaagcaagag atgagatttc cagtgctgac 660 tcggtggtgg aatgacttta gggcaggtat ttaacctcca cttccccaag tacacaagtt 720 atttcacaac tcttggcaaa aacagtgctg taaaaatcgt aagtttattt gttaaaaaaa 780 atactgtatt tgaaaagtac cttccttctg ggattttcaa ataatttgta cactacattt 840 tattcatcta cacattggaa atgagtaaac tggtgaacat atagcttttt atacatttaa 900 cacaaccagt gcaaattctc ctgcctctga gaaggcagag aagcccttta ctcagaaggt 960 cttcaattct agcattactc caactcctag ggaaatttcg ggtgggtgcc tatggctgta 1020 tgaccatctg attcctcagg gacaggacag gaattcagca agggagctta aaatatttta 1080 agtaattgtc aacattccat ggtgactctc cccaaaaatc tagtggtagg aaaataatct 1140 gtacttattc ctctttctgc acacaaagcc ctcatttaaa tttgtgagcc tgcttgggat 1200 ccattaccta gccattcaga gatcctgtca aatgcacagc agattggata ctcaccatcc 1260 caaaggggtt cctcccacct ggatggggcc aatctctagt tgacagtgcc cctcagagtg 1320 caccatggag atggaatgtc ccttccagag agacttttac acagggaaaa gcatttgttg 1380 gctgggctcc aactctcatt tggtacaaaa agctttacat tcttttccct ttttacatta 1440 cattcttcaa agacttccgt gcttgccagc tggataacaa ctcaagctct agtgtttact 1500 cttgcacagc cccaaaccct tggaaactca gcttcgttct atcagtgaca tcacccattg 1560 tggccgagga accacaaaac cttaaaatac aggcttaaat tcagcaagcg aagaacattc 1620 catattgaat gggcatgaga tatgcctatc agattgtgtg tgtgtgcgcg ttttttaaag 1680 acagccaatt acatcgtatc tagtcaaatg agcggattct aaagcagcct gctgggatgt 1740 tccacttagt ctaatgctgt tgccactgta cgccacagca ccggacagtg ttctttggga 1800 catctctggg aaatgctctg gaacatgctc cttgatggaa aacactaatt tttgaaagaa 1860 gtagatgtct ggaggcaggt ctggtgaata aactgaatag tactgccttg gaccccagct 1920 gaggggtggc agtaagcaat gaggatgggc tataaagctg ttaactggct aagggccatc 1980 cttgggcagg catttcagac acatctgtag agagggcagt agcatctccg ataggccagc 2040 tctgaaggaa gcttaatgct taatacagtc acactgcata aattagctta gaatgctctc 2100 ttgggtaaaa aatattaata gtgtatatgc acttgaaaag caaaattcct caagaaaaaa 2160 agtttaatag caaggagttt ccatcagtcc cggtctttgt gaggattacc acaacaaaca 2220 cttaaaagga tacaacaggt acttattaaa tgctgccttg ccttttacct cttccttttt 2280 tttttttttt tgagatggag tctcgctctg ctgcccagcc tgaagtgcag tggtgtgatc 2340 tcggctcact gcaacctccg ccttccaggt ttaggtgatt ctcttgcctc ggcctcccga 2400 gtagctggga tggactacag gcacatgtca ccatgcccag ctaatttttt gtatttttag 2460 tagagacggg gtttctgtgt tagccaggac ggtctggatc tcctgatttc atgatccgcc 2520 cgcctcggcc tccctaccct cgtgccgaat tctt 2554 72 583 DNA Homo sapien 72 cagatcatga agcaattatc ttcctggaag ggtttttagc tatgctctcc agttgcctca 60 gcagctttgg ctctgatgcc acagtgagcc caaggtggaa ggtgatggaa cagcatcaca 120 tctgcaggct cagtgtgtcg taaggtgagg gtaaggggag ggcaagtgta gacggatgaa 180 gaagatttct ccctattgct tccattttga tatttcttta acttcacatt tcatccatca 240 ttcctagaca gttgcctagt tatagaggat ttcttttatc ttttttatca gaggcatgcc 300 aggtggaagt gaggctgctg ctggcctaca actccagtgc tcgcattcca aaatgcccct 360 ggatggaggg tggtgagatg tcaacacagg tggaaaacag atccgagggc accataccca 420 tacagacaac ctgtaaaagt cataataaag ccccacactg cacggagcta aggcacaaac 480 aacgcttccc aaccgatggc taagggccaa ctaggcggca gatgagcaag ccgaagcatc 540 accgaaatga agcagctcag aagaggacct aagccccggg aca 583 73 981 DNA Homo sapien 73 gaaagaatga gatgttttca gacattttag gtccctgaga catgttcctg ttcattggcc 60 agaaactttt tggcgaacca cttcctattc aaaggcttcc tctccactaa taaagtagtc 120 tgtggtacat gcagccctga ggcttgagat ggaactgcgc aggaagagcc caactgggta 180 tcagaataag ccacatgcac cttctgaaac tgcccaaatc cacacctgca taagaatttg 240 agcccagttc ataaagcaga tcatgaagca attatcttcc tggaagggtt tttagcttgc 300 tctccagttg cctcagcagc tttggctctg tgccacagtg agcccaaggg gaaggtgatg 360 gaacagcatc acatctgcag gctcagtgtt ttgtttggtg agggtaaggg gagggaatgt 420 agacggatga agaaatttct ccctactgct tccattttga tatttcttta acttcacatt 480 tcatcctcat tcctagcagt tgcctagtta tagaggattt cttttatctt tttttcagag 540 gcatgccagg tggaagtgag gctgctgctg gcctacaact ccagtgctcg cattccaaaa 600 tgcccctgga tggagggtgg tgagatgtca ccacaggtgg aaaccagcat cgagggcacc 660 attcccttca gcaagcctgt aaaagtttat ataatgccca aacctgcacg gcgctaaggc 720 aaaaacagtc ttcccaaccg tggcctagag ggcccttctt aggtgtcaga atgagccaag 780 cctgaagcac ttcacctgga attgatgtgt aggcttaagg agtatgtgac ccttacagtc 840 tcatctggta tcaaacacag gataaattgt ttcttcatta aaaaataaaa aaccttcaag 900 tctacttacc cttctcctgt ccacaataaa gttgagaaaa caaaaaaaaa aaaaaaaaaa 960 aagatcttta attaagcggc c 981 74 401 DNA Homo sapien 74 gccgcccggg caggtaccag gcagagggag gagcaccaag gtgggggata tttaggggac 60 ctctttcctt caggaccaca cccttctagg tgaaagcacg aacacttgat tactttgcat 120 tccatctgca aaaacaaatt taggttttga atatggtgaa aaacgaagaa aggaaaatat 180 aaaactctgt attttatata cagtaaggaa taatggaggc tgataatgat cttgtgatca 240 gctaagacaa tgtcagtaag caggtgaggt agggtgcttt ctatgggcaa aagggtgaat 300 atcttgaatg accagaaatg actcgaagag ctgcattact atcatggtag catgcatgaa 360 gtgatacatc taaacctttg ctaacctaac attattactc t 401 75 1847 DNA Homo sapien 75 gccgatcttt tttttttttt ttttttattt ataaatttat tgcctgtttt attataacaa 60 cattatactg tttatggttt aatacatatg gttcaaaatg tataatacat caagtagtac 120 agttttaaaa ttttatgctt aaaacaagtt ttgtgtaaaa aatgcagata cattttacat 180 ggcaaatcaa tttttaagtc atcctaaaga ttgatttttt tttgaaattt aaaaacacat 240 ttaatttcaa tttctctctt atataacctt tattactata gcatggtttc cactacagtt 300 taacaatgca gcaaaattcc catttcacgg taaattgggt tttaagcggc aaggttaaaa 360 tgctttgagg atcctgaata cacctttgaa cttcaaatga aggttatggt tgttaattta 420 accctcatgc ataagcagag gcacaagtta gctgcatgtg ctctagactg tagagcgagc 480 caccgttgag aagcaaagga cagcagcagg aagagcaatg gaacctcctc aggacttacc 540 aggctgctgc acaggatcta gcttctccca cctaagatgg gcacattgaa agccttgttg 600 cagcagcacc cccatctgtg gaagcacagg ctgcctgcac ttctccagct gctctagcac 660 ctgacttcct ggtagtcagg gtaccaggga gagggaggag caccagggtg ggggatattt 720 aggggacctc tttccttcag gaccacaccc ttctaggtga aagcacaaac acttgattac 780 tttgcattcc atctgcaaaa acaaatttag gttttgaata tggtgaaaaa cgaagaaagg 840 aaaatataaa actctgtatt ttatatacag taaggaataa tggaggctga taatgatctt 900 gtgatcagct aagacaatgt cagtaagcag gtgaggtagg gtgctttcta tgggcaaaag 960 ggcgaatatc ttgaatgacc agaaatgact cgaagagctg cattactatc atggtagcat 1020 gcatgaagtg atacatctaa acctttgcta acctaacatt attactctca agctttatta 1080 tcctcaaggc ttaaatggct gtagctgttt aatttaaaag caaggcttaa aaaatagagg 1140 ttactcataa ttccctttcc atatcccttt ttgacttgaa aattatttca ccaactactt 1200 ttctggaatg ctgcttataa tacatattca cagattgccc tatgtgttat tctagtcatt 1260 ggcccgtttt gcttataaaa aaggccatgt tttgtattcc tacaaaatct gcagacattg 1320 ttaacataat acacgtcatt atacatcata tgtatgctac atctactcac tgacatttaa 1380 aaaatgagct attttcaaag actaacacag gatctgttac tgagacgtgt aggaaggagc 1440 tcagtgtaaa atattttctt tggatagatc ccttcaaagg gattaaaaca cacaaaatat 1500 tatttatact aaactttctt aaatgttcta tgatatttct atttcaaaat tctcttattg 1560 tgagaatatg tgaaatatag atgtagcaaa ttcaacacat aagcttatac cccttagctt 1620 gagtaaaaga cacatatatg gcttcccagc accaagaaga tggaagaaac tctactgcaa 1680 ctacttccct ttttccaagc agctcaaaat gctttagcaa ataccttgtg attctttttt 1740 tttttttttt ttttgagacg gagtctcgct ctgtcgccca ggccggactg cggactgcag 1800 tggcgcaatc tcggctcact gcaagccgcc ctcgtgccga attctat 1847 76 522 DNA Homo sapien 76 attttactct agtattaatg tggttttata aatgattata tgccttatat tctgggggga 60 aagaaatgtg aaaatgtgct aacgtagaca gaaacagaat atataagtcg ttttgaatgt 120 tatttctttt ttaaaaaatt tgcttggtgt catatagcca aaactattca tggtgacagt 180 ttcattgcta tactttttat atgatttcag cgaattgaaa acatgtatat aatagcaaaa 240 aactggactt catgctgagt atagatgata catataaaag aagtcaaaat ttggagaaaa 300 aatttaaaaa gataagtaga aaaatgaagt aactgtagaa accatactta ctctttgatc 360 tcaaatgctc aaaaactgaa tgaaaatgtg aatttaggcc gaccaggtag tcttgtcaat 420 aaactaaaag caaaaacagg aaaattgaga aatatgttac aactataaca acacaaaaca 480 gcatagtttt gaaacacttg cagttcttaa atataaaagc tt 522 77 1643 DNA Homo sapien 77 actgtcaatc atcaattgac attaacatgg tcaattaagt aatgtttctc acccaacttt 60 aaatttccat agtcataacc atggaaacat acaaaaaaca aacatgcaaa taaaatgtca 120 aaataattga gctgagtact ttgcatgctt taggaaataa gatgtagggt ggttctttgt 180 gccaatatat tcaagtaatt ggtttatctt cccatgtttt gctgctctaa acatgatcta 240 atataactct cattcatgtt gacatagcag agagctgcta ggagtaaacc tgttttctac 300 acattaatca agctgttctt tcaaagtatt gtttgacaca ttgaatgttt tttattctgg 360 aatattatca cagcaaaacc tcattaattg gatgctatca aaattatgaa aggaaatctg 420 agtgagcaca cttgttttga aaagaaattg gtaaatactt ctatgatgca gttttaagtt 480 atacaattaa ctgctatttg gaatttaata agtccactat aagcaatgtg cctgcacacc 540 aattaaaggt tggatctgtc tcttcttgac aattttttag aagccattat ttcgttacca 600 aataaacctg aagttaagaa atatttatat ttacatctat ttatatctgt tggagaatat 660 ttcataactc agacttggtt gttttacaca gacttctccc cattatccaa catagtgaga 720 tttttctata gttctatatt ttactctagt attaatgtgg ttttataaat gattatatgc 780 cttatattct ggggggaaag aaatgtgaaa atgtgctaag tagacagaaa cagaatatat 840 aagttgtttt gaatgttatt tcttttttaa aaaatttgct tggtgtcata tagccaaaac 900 tattcatggt gacagtttca ttgcttactt tttatatgat ttcagcgaat tgaaaacatg 960 tatataatag aaaaaactgg acttcatgct gagtatagat gatacatata aaagaagtca 1020 aaatttggag aaaaaattta aaaagataag tagaaaaatg aagtaactgt agaaaccata 1080 cttactcttt gatctcaaat gcccaaaaac tgaatgaaaa tgtgaattta ggccgaccag 1140 gtagtcttgt caataaacta aaagaaaaac aggaaaattg agaaatatgt tacaactata 1200 acaacacaaa acagcatagt tttgaaacac ttgcagttct taaatataaa agcttttatt 1260 agttaatttt ttaaaaggat ctcataggat tgacactgaa tcaggttggg aggtggaata 1320 agggtgatgg catattcttt ctgaattact tattataaca tttctagaat cattaggtca 1380 gtgctacttt gttgtcgtca atgtacaata aaggaatcac aaattgatct tagtgataat 1440 tttacagagg cagacattgc acataggtat gactgcaaaa atgggtggct aactctggga 1500 agatacttgt gttaaacttt atatgacatt taataaccct tcatcataag gcaatgtttt 1560 ttacaaaaag attgcacaaa atcatgttag tcatttactc tgcaaaaatg gcacattagt 1620 gggggttcca aaatccataa tga 1643 78 755 DNA Homo sapien 78 cgaggtataa aaactacgtc actctaaaat gttacaaata ggtcatctac ttagtatgca 60 tagccttgat aaaaacattg gtcaagtcgg gatgtagtcg gccaccaact agaaatgtgt 120 taagattttt ttaagcagac ttgcttaata aggcaaggag tggggtcagg ttgttctagg 180 ggccagcaga agggtctaaa atacagggta gtgaaaagag attacgagac tagtgagttt 240 cctttaaatg cttaactagt cattattaag acagccacat ttcagtgggg ctgagccaaa 300 ctgctgagct tggaatagca tatgcttgga atctgaatat gaataaggcc caggtgccac 360 actttacacc acagatcctt tgctaaagag gcactatttt gtctaacagg caaggaccag 420 gctggcagtc aggaaggctg ggtttcggtg ctgatcttgt caccaactat gcactcttga 480 acaagtcact tcacttcact atcctaagcc tgttatctca tctgaacaaa taacaggggt 540 tagacttagc cttttacaat gacattttgt atatatctac tgagctctaa caattattac 600 aacatatcta tgtctgacag ataggatagt cctacatatt caggaaactc cacgtatagc 660 tctcctaaaa ctgattgttg cgtgttacca cacaacacaa caacatacaa acctgggcac 720 tggcaacacg accggtcaat tctcccaaca caacc 755 79 1002 DNA Homo sapien 79 tatttcatct ttatagggaa tttgctccca aggtatattc ggcacgagaa aaaacctcat 60 atttaaaaac tacgtcactc taaaatgtta caaataggtc atcttcttag tatgcatagc 120 cttgataaaa acattggtca agtcgggatg tagtcggcca ccaactagaa atgtgttaag 180 atttttttaa gcagacttgc ttaataaggc aaggagtggg gtcaggttgt tctaggggcc 240 agcagaaggg tctaaaatac agggtagtga aaagagatta cgagactagt gagtttcctt 300 taaatgctta actagtcatt attaagacag ccacatttca gtggggctga gccaaactgc 360 tgagcttgga atagcatatg cttggaatct gaatatgaat aaggcccagg tgccacactt 420 tacaccacag atcctttgct aaagaggcac tatttgtcta acaggcaagg accaggctgg 480 cagtcaggaa ggctgggttt tggtgctgat cttgtcacca actatgcact cttgaacaag 540 tcacttcact tcactatcct aagcctgttt tctcatctga aaaataaagg ggttagactt 600 agccttttaa atgacatttt tgtatatttc tactggctat aaaattatta caaatatcta 660 tgtctgacgg taagatagtc taaatattca ggaaaactcc aagtatagct ctcctaaaaa 720 tgatatgttg cgtgttaaaa aaagaaaaaa aagaaaagaa gaagggggag gaaaaaataa 780 aatgaaaaaa acttcaaaaa tgcacggctg agttggtagc aaagaaggaa attctttgga 840 ggccaaaaag atctagaaag tttaaatcca atgtgcagga gctggcattg cctagctaat 900 ccctcatgat tgagaacctc agattataga cactcatggg gaccaagaga taaggcctgg 960 ggcctcaaaa aggccagagc cgaggtcgga tcaaagaatc cc 1002 80 374 DNA Homo sapien 80 tcttttctaa aactttaatt tccactatgg ctcttttgaa accattttaa tcaagtcaca 60 tttcttagaa aaaattcact cagggttctg aaggaattag ttattttcta caagcaactc 120 tgtcatgagt gatagagttg tagctctctt agaagttttt ttcccctttc aaagagaatg 180 agaaatatgc agagatttcc ttactgactc actaaatgta aagattaaga ggacataata 240 aaatttggga ctacagtagc atataggttt tcagtttatt tactactaac tagctataac 300 ttagacaagt catttaacat gctgtgcttt agtttcatct ttgaaaccaa agagattcga 360 accagaaatc tctt 374 81 399 DNA Homo sapien 81 atggggaatt ccattgacac agtcagatat ggcaaagaat cagatttagg ggatgttagt 60 gaagaacatg gtgaatggaa taaggaaagc tcaaataacg agcaggacaa tagtctgctt 120 gaacagtatt taacttcagt tcaacagctg gaagatgctg atgagaggac caattttgat 180 acagagacaa gagatagcaa acttcacatt gcttgtttcc cagtacagtt agatacattg 240 tctgacggtg cttctgtaga tgagagtcat ggcatatctc ctcctttgca aggtgaaatt 300 agccagacac aagagaattc taaattaaat gcagaagttc aagggcagca gccagaatgt 360 gattctacat ttcagctatt gcatgttggt gttactgtg 399 82 517 DNA Homo sapien 82 gaaagtatat tgacgtaggt agtggagacg ccatgagttc ataatctgtc cagagtcgca 60 gtatgatgta tccggcaccc gacaggtcaa gaaagaacta cttgtttcta ggaagaacat 120 atgaagtgct taatttataa gcgggctgtc gaatattatc caatatagtt tcttctgaaa 180 agtgaaaggg gatcatctat tgttagatta gggggtctcg gaaacttttt gaaaattcga 240 atcagtggac caatgtacat gtgaaaacta aagagggcag gggttaaaat agggcttgaa 300 tttctcattc tgtatagacc agcaaacttc cctgtgcaag gcaagtttac atcacaaatc 360 caagaatgtt tgcatcctaa atgctagttt gcttcagccc ctagttaacc tcaggacttg 420 gtttgcatat aaaaggtaga cagctgatat gttttcatga ataaatattg tcagccagaa 480 aaggttggtg tcaggtaatg catatttttt taagctt 517 83 619 DNA Homo sapien 83 acacaatgat acccattttt gcatgttaat gtattattaa atatcagtgg gaatagtctg 60 catgctattt cacatctcag gcacacttaa ggaagacctt gtgatgtgca tgttgctcat 120 ttaatctaga aaggatacca agattcattt agaacttctt tatgcacagt ttttttttga 180 gtatgttatg tcctgaggca ttaagggtat tactaaagca agcagcggga cttctcagag 240 aaattaaagg tttcatatca accacacgtt gtcaaaatct tcactttgaa taggattaaa 300 tgatgtttca tcagtattct tggcacacat gacattgttt ttaaaataac agttttatta 360 ctctgggctg tgacagtttc tcagactttc cttaatatca tacaattctc caatttaaac 420 tggtatagtc agttttacaa tattttaatt accctgtatt cattagcact ttcctcattt 480 tctactacct cctccccagc tgcccctacc ctaggcaatg ccaaatctac tttctgtcta 540 tatatttgcc tattcttgaa atttcaaata aatggaatcg tataatacaa acaaaaaaca 600 ggaaaaaaaa aaaaaaaag 619 84 646 DNA Homo sapien 84 aatgatccat ataggcgaat ggtcatctaa atcatgctcg agcggcgcag tgtgatggat 60 cggcgccggg caggtaactc accccccagg atagagaagt gtttgttagg gagagaagag 120 ggagaggcag gagccggccc aagcccaggg tccctgcttg ggccccagaa agcacttaac 180 caggccccaa gccttcaagg gaaaccaagg cctcaaccag acaatcttga gggaaggaaa 240 agccagactt tgggtttgtt ttttggggga attattggtt tttttttttt tatgtttctt 300 ttggaatttt gtttgttggc aaattctgtg tgatcttttt tcataaaaaa aaagacaaag 360 aatttacatt ggacaaaatt aaaaaaaaac aaaaaaacaa aacaaaacaa acaggcgtgg 420 gcggtctacc tcaggtggcc atatgccggt gtgtcccggt ggtggtgaaa catgtggtgt 480 tatctccggc ctcaacaaat tctcccccac aacaattccg tccaccgcac caagcccgat 540 ctaacaacag gacatcatat agcaacctat atacgagcac ctcaacagca ccaacgacag 600 ccaagcgaga cgaacgacca acagacacac cactcacaac caaagc 646 85 419 DNA Homo sapien 85 cggccgccgg gcaggtactt tcgttgatac aggcgtggaa gaccttgagt tcccctgtgg 60 ctaccccatc atagttcctc ctaaggctat accagataag ccatacggag cagatgacca 120 gcaagaacct ttccagaatt attattctaa ctagaatctt agccaagaga atggaatcac 180 cacaaatgtt atcatgaaaa tcatctcaag taaatttcct attccattca taccgttaag 240 ttgaggctcg atgatatacg aaaactttaa ctgaattgac ttcataaagg cttaatggtc 300 ttcaaaatta tgctggttat atgaattctt aaattcaagc tcttttccaa ataataaatg 360 ataaaacaac attttaatta gtattttacg taaaaatata tattaaaaag taaatcaag 419 86 2133 DNA Homo sapien 86 ggaagtacag gataatatta aagtcaaata gagtacagtt cttcagcatc ataaatcaaa 60 attcaattgc tacaaaaatc aaaacttgtc agactttttg ctttaataca aatagttgga 120 atttctgagc aatcaggttt atctttaaat atgttttttt ctgagctttt ttacttcaaa 180 aacgatgaga attatcaatt tttcagtact actgacttgt tccttgtgga aggagggaac 240 attaagtatt taaatcaatt tcttaagtct tcgagtatca aatttatttt gtttaatctt 300 tgatttaatg tttaacatgg gcacttttta tattctctta cctgagttag ttttgaattc 360 ctagaacatg tccattttaa cagtggttgt gatattattt agttaatact actgtctgga 420 ttattttaaa atcttggtac aatttgtata aaacaacata acacttgtta acttgccagt 480 cctctaggaa cttgtttcct ttccttactc tgaatagact agtggtagct gtccattatc 540 ttttacctta attacgattg tttgaaccac atttaaattc caaaatctat attattggtt 600 taaaagcttc aacttgacaa gatattatta acagtctaca tgaaatcctc aaattatata 660 tgaattttca aacattgata tcagctcctt gatttacttt ttaatatata tttttacgta 720 aaatactaat taaaatgttg ttttatcatt tattatttgg aaaagagctt gaatttaaga 780 attcatataa ccagcataat tttgaagacc attaagcctt tatgaagtca attcagttaa 840 agttttcgta tatcatcgag cctcaactta acggtatgaa tggaatagga aatttacttg 900 agatgatttt catgataaca tttgtggtga ttccattctc ttggctaaga ttctagttag 960 aataataatt ctggaaaggt tcttgctggt catctgctcc gtatggctta tctggtatag 1020 ccttaggagg aactatgatg gggtagccaa aggggaactc aaggtcttcc acccctgtat 1080 caacgaaagt actctaatgt ctgttttaca tactgggatt atttgtaaga tttcatttga 1140 aaggaaggtt ctttagacca agaaagaaaa ggaaaaaggt tgaaaccaat gacctgctcc 1200 aatctcttag aaactgaatc tcagagaagt taacttcaag gtaaaagcat ttgttagtgc 1260 tagaggtaag atgaaaattc aagttttttt attccttgtc ttcataataa tataattatt 1320 gtgatgtctt ttgtacaatt tgcataatac tatgtataca ttcacatgta gtatttaagt 1380 tacataagtg atgggtacta tgaaattact attgatcaag aatgactatt agattttaat 1440 taagattaca ctttatttct tgtaaaaggt gatttaaaat gcacattcct taccaatcta 1500 atttgaatca tgattagcct cagtttaatt atccttacaa aaatattttt gagtggttgg 1560 gatcagtttt aagttgagct cctagatttg ttgaatagga aaggatacta ataactgttc 1620 taggggaaat gattttgtaa tatttcacct tgaatttttg aactgaacct tataaactag 1680 tcttcagaat gactaagcag gttaaatgtt ttagcattta aatgtcaaat agagaaatca 1740 atctgacttt tggaaaaaag aaagatgttt aatttaaaat atgtaaagca aacttccaaa 1800 tttcttccat cagtaagagt aactaactgt ctgaatgtag ttattattat tgtgtcaagt 1860 taaatgattg tacatacttt cctttacaga tttggataag tgaagacagt aataacattg 1920 aagcagtgaa ccagtggaaa gagacagtaa taaatccaga aaaggttgtt atcaggtggc 1980 acaaattaaa tccatcttga agacttcaca cattaatttg gtgaagaact tgacattctt 2040 ttagaagact tatgatttca atttgctacc aatgagaaga ggcaaatcaa caaatttgtc 2100 aatttatggg ggctataatt atggtatata atg 2133 87 493 DNA Homo sapien 87 gcggccgccg ggcaggtctt cgatctcccg gggtgctggg attacaggtg tgagccacag 60 cacctagcct taccttcaaa ttctaaacca agctatttaa atagccactg tttgattatt 120 tgaattaaca tggagcatct tctgggatat tgttcaggga aatatgagta gatcaaggta 180 ttttggggat gtaaaccctc atgtttgata aaataaatga tattttgagc tactgtttgc 240 tgggaacaga aagtaagaag ggaaaaggag cgaccataca ggaaagtaaa aataataaaa 300 gaaaatttag aaaactagag gaaaaggtat gaaaggataa atcctccatc ccatactgat 360 aatggccttt gagcatcact aagccccttt gcttctccca ttaagcaaag gatgatgact 420 gaggaggaac aaacaaaaat agacatcatt ataaaaaata cccaagactt ttagatgttt 480 ctctaacatt tgg 493 88 1412 DNA Homo sapien 88 tgaattagcc atacaaaaaa aataaaaaat tactgttagt caccctacag tgcaaggtaa 60 cactagaatt tatctttcca tctagtaacc actgtttttt aaagagacag agtatctccc 120 tgttgcccca gctggagtgc agtggcacaa tcatagttca ccacaccctg gaactcctgg 180 gctaagggat cctccttagc ctcagcctcc caagtagcta ggtatacagg catgtgctac 240 catgcctggc taattaaaaa agattttttt agagatgagg tcttgctgtg ttgcccaggc 300 tggtctcaaa ctcctgggct caaacaatcc tcccaccttg gcctcccaaa gtgctgggat 360 tacaggtgtg agccacagca cctagcctta ccttcaaatt ctaaaccaag ctatttaaat 420 agccactgtt tgattatttg aattaacatg gagcatcttc tgggatattg ttcagggaaa 480 tatgagtaga tcaaggtatt ttggggatgt aaaccctcat gtttgataaa ataaatgata 540 ttttgagcta gtgtttgctg ggaacagaaa gtaagaaggg aaaaggagcg accatacagg 600 aaagtaaaaa taataaaaga aaatttagaa aactagagga aaaggtatga aaggataaat 660 cctccatccc atactgataa tggcctttga gcatcactaa gcccctttgc ttctcccatt 720 aagcaaagga tgatgactga ggaggaacaa acaaaaatag acatcattag aaaaaatacc 780 caagactttt agatgtttct ctaacatttt ggggtcattt tcagattacc agtgttcatt 840 tgctgaggta tattaacgga tatttgtact taatttgaaa aatagcagga tccaaaccag 900 aggtctgtat aagagcaggc ggcatgcgtg tctggagagc tgctgcctcc acaagtattc 960 tgacagcact gggctgctag tgagacctgg atggccaccc tccccatgtc atggccatgg 1020 gttttcggga accgtttcct ccttttactg catcacagtt gcaaactcgt ctatttattt 1080 ttctcttgat taacaactgc actctgacat tgcagcagtg ttgatgaaga caatttaact 1140 catgtttttg ttaacataat aattgtctgt cgtaactaaa atataagttt cttgaaagct 1200 ataatcaggt atagagaaaa tctttgttat gcacaatacc agggcaggta atatctgtaa 1260 tatgtattaa cagcaattca ctaaacattg aatgtctctg tatgctggca cctgtgctaa 1320 agatttgctg tataaagata aataggaaat tgcctcttct cccacgaaac tcaaaacatt 1380 tattgaatga ataaataata ggtgaattaa ta 1412 89 624 DNA Homo sapien 89 ggtacttgag gtgtttctca ggttccagaa catccgtgtc atcttaccag atccttcaag 60 gattcagctt aaagatcagc tccaccagga agccttcctg gatttcccct cttagtttcc 120 aacaagaatc cggctcttcc gttctctgcc caccttggag tagcagtagc gttcagctgt 180 gagactctcc gtgtttttcc cgttacagtc gtttgttagc gtgcatcctc tttcgactga 240 attagttaga tgtgagaccc taggactctc ttgttttctt cgttacagtc tttgttgctg 300 catcctctct cactgaattg ttgaattgtg agaccctgtg agggtcggca ccctgtgata 360 ctggccagga aagggttgtt gcaaggggat catgggattg ttgaatgggt tttgatctgg 420 attttgatgt tggaaatcaa gttcccaaat gttttcaacc ttgggtaaag gaacatgtaa 480 tggtgttttt taacaaaaca aaaaattaaa aaaaaaaaaa aacaaacata aaaaacaacc 540 aacggctggg ggcacccggg ggcaaagggg gcccgggggg acattgtttt tcccggtaaa 600 atccccaaat tgggaaaaaa aagt 624 90 659 DNA Homo sapien 90 accacgcctg tagcctctgt ctagagtagt tcacacatgg atgctgtctc tctggtactt 60 gggtgtttct caggttccag aacatccgtt catcttacca gtccttcaag gttcagctta 120 aagatcagct ccaccaggaa gccttcctgg atttcccctc ttagtttcca acagaatccg 180 tctcttccgt tctctgccca ccttgagtag cagtagcttc agctgtagac tctcctgttt 240 ttcccttaca gtctttgttg ctgcatcctc tttcactgaa ttgttgatgt gagaccctag 300 actctcctgt tttttcgtta cagtctttgt tgctgcatcc tctctcactg aattgttgaa 360 ttgtgagacc ctgtgagggt cggcaccctg tgatactggc caggaaaggg ttgttgcaag 420 gggatcatgg gattgttgaa tgggttttga tctggatttt gatgttggaa atcaagttcc 480 caaatgtttt caaccttggg taaaggaaca tgtaatggtg ttttttaaca aaacaaaaaa 540 ttaaaaaaaa aaaaaaacaa acataaaaaa caaccaacgg ctgggggcac ccgggggcaa 600 agggggcccg gggggacatt gtttttcccg gtaaaatccc caaattggga aaaaaaagt 659 91 556 DNA Homo sapien 91 aattttcaac tggcccatac tttatagtga tggaaagcgc ataacactac ttgtaaatca 60 ttaaaatagg gtgataactg tgataatagt gtttcttgca ttctagaaaa ttattttatt 120 aactacattc aaaacccagc atttcacagg ttccatcatt agaaacagta tagttctagt 180 taacatgatt ggagagtttc aggggaaagg tttacatttt ctgaaactgt atttggtatg 240 tgactcaatg tggtatttca gtcttgttag tcacttacat gactgacgtt tgcaaggatt 300 tattgccaag taaaatttga tcagagtgca ctgagaatag ctacataagg ggaaatctct 360 caaaattcct tctgttcact ttaattcgga gcatatgttt caactcattt tcacacatct 420 gtcccacagt tgaagcatta acacacatct tcacgacaca atgaacacat acacattagc 480 aaacataagt ctcttaatgc aaaattacta gttgactaca atatagctac cttaaaagca 540 gagcttgcta taattc 556 92 635 DNA Homo sapien 92 acaaaatata atgttataaa tgtattttaa aaaaagaaat acaaattcta tggtcttttg 60 cattttactg cctcaaagca gaattagcaa agctgatgaa gaatgaacat tttcccttgg 120 gcgggtggcc cttggtcact cccacaggca cgttaccggg ctccggcgtg tgctcccacc 180 aaccacggca aacaaaggcg tcctcctcac ttgaagtcct ggcctgtggt tgtttcatct 240 gtttttttgc tcagtgaaca aaacgttctg aaattagaac tcaccaaagt taaaagcagt 300 aaaacaacat atgctactta agacattttg aagcggaaag taaagctatg tgaatgccgt 360 ccttccttcc ttcctttttc tacagcttgg aaacctctga gaatttgctg gcgggtggca 420 gaggagggct tcgtctagct cttgaacgga caggaactgt ctggctagac agctctccag 480 accacgaaag cccaggaggt gccctcttcc acacaacaga ctaagcactg cacccacttt 540 ctttgatcca gaaagcatcc ctactgaccc tgtaacctac accctctctg tccaaagaac 600 agaggccgac cagagtagcc agcctggaga ggcac 635 93 8156 DNA Homo sapien 93 cggggcgtgc gcgtcctcct ccccaggccc gccgcctccc tgccaagaat ctgagagagg 60 ccgagtggag ttcggtcctt ctctgaacag ttttagctga gagtaccagc atccaactgg 120 gagcgttgtc attgcatttc cacattccca ggaaagccca ggtgctggct gccagctgct 180 gcgcccccca tgtagaaggt gcacctcctg ggagcaggca cgtcttttgg ctcttctgac 240 catggagaga taggacggtc cctgcagccc gcgcgacaga aagctgtgcc gccaccaccg 300 gccgcgtccg tccttcggat ggatcgcaac agagaggccg agatggagct gaggcgaggc 360 cccagcccca ccagggccgg ccggggccac gaggtggatg gggacaaggc tacctgccac 420 acctgctgca tctgcggcaa gagcttcccc ttccagagct cgctttcgca gcacatgcgc 480 aagcacacgg gcgagaagcc ctacaagtgt ccctactgcg accaccgggc ttcccagaag 540 ggcaacctga agattcacat ccggagccac cgcacgggga ctctgattca gggacacgag 600 ccggaggcgg gcgaggcgcc gctgggtgag atgcgcgcct ccgagggcct ggacgcctgc 660 gccagcccca ccaagagcgc ctctgcctgc aaccggctgc tgaacggggc ctcgcaggcc 720 gacggcgcca gggtcctgaa cggggcctcg caggccgaca gcggcagagt cctgctgcgg 780 agcagcaaga agggggcaga ggggtccgca tgcgccccgg gggaggccaa ggcagcggtc 840 cagtgctcct tctgcaagag ccagttcgag cgtaagaagg acctggagct gcacgtgcac 900 caggcgcaca agccgttcaa gtgcaggctg tgcagctacg cgacgctgcg ggaggagtcg 960 ctgctgagcc acatcgagag ggaccacatc accgcgcagg ggcccggcag cggcgaggcc 1020 tgcgtggaga acggcaagcc cgagctgagc cccggggagt tcccgtgcga ggtgtgtggc 1080 caggccttca gccagacctg gttcctgaag gcgcacatga agaagcaccg gggctccttc 1140 gaccacggct gccacatctg cggccgtagg ttcaaggagc cctggttcct caagaaccac 1200 atgaaggcgc acggccccaa gacgggcagc aagaacaggc ccaagagtga gctggacccc 1260 atcgccacca tcaacaacgt ggtccaggag gaggtgatcg tcgccggcct gagcctctac 1320 gaggtctgcg ccaagtgcgg gaacctgttt acaaacctgg acagcttgaa cgcccacaat 1380 gccatccacc gcagagtcga ggccagccgc acgcgcgccc cggccgagga gggggcggag 1440 gggccctcgg acaccaagca gttctttctc cagtgcctga acctgaggcc gtcggcggcc 1500 ggcgactcgt gccctggcac gcaggccgga cggcgggtgg ctgagctgga cccggtcaac 1560 agctaccagg cctggcagct ggccacgcgg ggtaaggtgg ccgagccggc cgagtacctc 1620 aagtacgggg cctgggacga ggcgctggcc ggggacgtgg ccttcgacaa ggacaggcgc 1680 gagtacgtcc tggtgagcca ggagaagcgc aagcgtgagc aggatgcacc agccgcgcag 1740 gggcccccgc ggaagcgcgc gagcgggcct ggggaccccg cgcccgccgg ccacctcgat 1800 ccccgctcgg ccgcgcgccc caaccgcagg gccgcagcca ccaccggcca gggcaagtcc 1860 tccgagtgct tcgagtgcgg caagatcttc cgcacctatc atcagatggt gctgcactca 1920 cgcgtgcatc gccgcgcgcg ccgcgagagg gacagtgacg gggacagggc ggcgcgggcc 1980 cgctgcggat cactcagtga gggtgactcg gcctcccagc ccagcagccc tggctccgcc 2040 tgtgccgctg ctgactcccc gggctctggc ctggccgacg aggctgccga agacagtggt 2100 gaggagggcg cccctgaacc tgcaccaggg ggacagccgc gccgctgctg cttttccgaa 2160 gaggtgactt cgaccgagct ctccagtgga gaccagagtc acaagatggg agataacgcc 2220 tcggaaagag acaccggcga gtccaaggca gggatcgcag cttctgtgtc catacttgaa 2280 aacagtagca gagagacttc tagaaggcaa gagcagcaca gattttctat ggacttaaag 2340 atgccagcat ttcaccccaa gcaggaggtg cccgtccctg gtgatggtgt ggagttccct 2400 tccagtacgg gagcggaggg ccagacgggt caccctgcag aaaagctgtc cgatttgcac 2460 aacaaggaac actctggggg agggaagcgg gcgctggccc cagacctcat gccgctagat 2520 ttaagtgcga ggtcgacgcg ggatgacccc agcaataagg agacggcctc ctccctgcag 2580 gcggctttag tcgttcaccc gtgtccttac tgcagccaca agacctacta ccccgaggtc 2640 ctgtggatgc acaaacgcat ctggcaccgt gtcagctgca actccgtggc tcccccgtgg 2700 attcagccca atggttacaa aagcatcaga agcaatttgg ttttcctttc ccggagcgga 2760 cgcacgggcc ccccgcctgc cctcggtggc aaagaatgcc agcctttgct ccttgctcgg 2820 ttcacccgca ctcaggtgcc aggggggatg ccggggtcca aaagtggctc ttctcccctg 2880 ggagtggtca caaaagccgc tagcatgcct aagaataagg agagccattc cggaggtccc 2940 tgcgctctgt gggcgcccgg ccctgacggg tatcgacaga ccaaaccttg tcacggccag 3000 gagccacatg gcgcggccac acaggggccc ctggccaagc ccaggcagga ggctagctcc 3060 aaaccggtgc ctgccccggg tggcgggggc ttcagcagga gcgccacccc tacgcccacc 3120 gtcatcgccc gggctggcgc gcagccctcg gccaatagca agcctgtgga gaagtttggg 3180 gtccccccag cgggggctgg ctttgccccc acaaataagc acagtgcccc ggactccctg 3240 aaagccaaat tcagtgctca gcctcagggt ccacctcctg caaagggcga agggggcgct 3300 cctcctctac ctccccgcga gcccccctcg aaggcagccc aggagctgag gactctggcc 3360 acctgtgctg cggggtccag gggcgacgcg gccttgcagg cccagcccgg cgtggctggg 3420 gcgccccccc gtcctacact ccatcaaaca ggagccagtg gccgaggggc atgagaagcg 3480 cctggacatc ctcaacatct ttaagacgta cattccaaag gactttgcga ccctctacca 3540 gggatggggt gtcagcggcc ctgggttgga gcacagaggg acactccgga cgcaggcccg 3600 gccaggagag ttcgtctgca tcgagtgcgg aaagagcttc caccagcccg gccacctcag 3660 ggcccacatg cgggcacact cagtggtgtt tgagtccgat gggcctcggg gttctgaagt 3720 tcataccacc tccgcagacg cccccaaaca agggagagac cattctaaca caggtaccgt 3780 ccagacagtg cctctgagaa agggaaccta aaggcgtgtt tccgacgcac cccaggtccc 3840 cgtaacggcc attagcagta ccctcacgat gtcccagcag cctcccacct gtgacctggc 3900 cgctccatgg aagaacagcc ggggaactcc tgagcagaca cctcacatcc cgagccgctg 3960 cgctggagtg gaaactgaag gcagatgcct ctccttgtta aacgttcaga aataaatgaa 4020 gatgctatat tctagaaata catgtagata ctatatacgc atttacgtgc tcatcgtcca 4080 tagtcccata ttttcttata ataaacagta gtactggcag gcacagtagg ggcacaaggc 4140 atctgtctta ttcaagacaa gtttgagaca ctggaaaaaa agatacttgt tgtgtgtgtt 4200 ggacagagtg gcgaggctga gcactgtcac aggggcctcc catgttaaga gggactgtgg 4260 ggatgatgtc agaacaagac gtggtggatt tgaggttgat cgagtattaa tactactgcc 4320 tctccttgtc ttagtgggta tttaaaatag taaataagag agaggaagga ggtgacgttc 4380 aggtgctgtg ggaagcaggc ttggcggagg ggtatgatga tgagaccctc attgttcact 4440 ggctccatcg cactcctccc tggggccgtg tgcctgttcc attcttccca ccattcgaac 4500 tgagcgaatc tggcaaagga gacacgtctg tgggaatgcg tagattccgc ctcggaagag 4560 agctagcgca acactaagaa aagcaggctt cttgtttatt ctcaggacct ttttgtaaca 4620 gggctacatt ctgcaaactg cttacaaagg aagactatac gtcttaacaa attatttagc 4680 cactgagtcc tcccgattcg gacctgtttt agtaatggca gaagaatccc tgagcaggtt 4740 caggtgccct agatgactag ggtgctgagc tctggcgcct tctgtcccca ctctttgcct 4800 ccccgcccct tccctgagcc accccagcaa gtgggtgtct tttctccctg ggcctggtga 4860 cctccacagg atgagtgact ttgttcataa agggtgggga tcaccagccc cttgggtggg 4920 ggacggcttc atatacctct tcctcagtaa tgcaaatgcg agtttttgtg gtgggggtta 4980 aggcccataa caaaggatct taaaccatgc agtgtacgca attgaaatgg tattccacag 5040 atataaatat tttcttttcc cattgccgtg acactatgtg tgatggtaat atttctgaga 5100 gtttcagatt tttgcacata tgattttatg cattatcaaa agttactgct gccttgaatg 5160 aaaatgttct gtgaaatttt ttgcaaaagc tttactaggt ttttttttaa ttgtgaaatt 5220 ttgtaaaggc aggaaatgga ttaaaacgag catgctaaat atatttttca aaaaagcaat 5280 aattttacat gtacagaaat tatcctaacc tttaatactg gcgagagcaa cagtttactt 5340 aatacggtaa tggactagtg cagtttttgt agacagtggg cttctgatac aaagtcttgt 5400 ttaaacacag acacacacac acacaaacac acacacacac cctaaagtgt gggtttcctg 5460 ttctaatgat ttgttgaata ttattatatt attattatta ttattattat tattgttatt 5520 gttattagta atgtttggtt ctggattcta cttgttactg agtttaaatt acttgacggt 5580 tcaggttact ttgcaacact ttcaaacgat gcaatgtaac tggctagctt atatatatat 5640 atatatatat atatatatat attttttttt ttttttactt atttttttct gatattctta 5700 caccagatat gtacgaaaat gatctgtcct gttggtgtaa ttaggaatgt ccatgcagat 5760 acagttaaac aactgtaatt gactgttctg taaagttatt ttgggcaaag ttgcggagac 5820 acattcctct gtccacctaa gaaatcagaa gactcttctg ttgatttatg tttaatcatt 5880 tcagtagttt ccccacagtg atcatttctg cattttctgg cttttgtttt cttggctgaa 5940 agtgaatggt gactgttagg aatgtcaggg actagtgacc cagtcctgtt tctctgtgtt 6000 ttagttatta aaaagaaatt ctgtacccaa agtgacacga aagtgtagtc tacattttta 6060 ctgtttcaga agcggcatgg aaaagtgcag ttggcctttg gagctggaag tgtcttgctg 6120 gtgaggctcc atcctggagg ctctggtggg gagtgggctg gcgctggggc cctgccggcc 6180 gcgtgctgga tccttcctgg cttgcaggag agcaggcgtg gaggacagtc agcttgcggg 6240 gccgcgcagg gtgcacagag tgcaggagga aggttttcac ccagttaaac agactgggga 6300 gcccccccaa gaacgccatc ccttgaggcc agctgtgggc aggcctggat gtgtggtccc 6360 ttccttccac ccatcgtcag tattgtgttg gtttgttaat ttgttgattt ggtcatagta 6420 tttaatatga tttgtgtttc cttatttatt tagccaccgt tttgattgcc tttttttttc 6480 cgaatggtaa tttctgcatg atacacttct gtacgttgtc ttctgactgt tacagacttt 6540 ctactacctc tcccgatctg ctgtttcctt gtttcttaac aggatttttt acagtgttgc 6600 gtctaatgta acttagacaa taaagggttt ggttgtctac actgcagctt ctcggtgtct 6660 ctcccctgct ttccgctcgc tgcttcccgc tctgcccctg ctggggcctg gctgcaccct 6720 ggcctgcctt cctatactct cctgtttccc gctcatatct cttcctcatt tttgcgttca 6780 aataacacac agctaatgag cttctaaaaa tcttttcagg ttgttcactt gtattcctta 6840 atttgaagaa tgaatattta aattctctca aaagtcagat attgaggatc ttctctggga 6900 aattggccac tgtacctgcc cacctttctg cctggttccc tggaaggtct tattgtcatc 6960 ttagacggac agatttcatt ctcagcacca tacagatttg gcttcaaagc caggtgaatt 7020 ttgcctttga ggctctgaaa agtattaagt gttttaagag gtcccccaat atttacttat 7080 ttatttttta aaccaagaaa gacactggtt ccctgaaaag caggtgcttc aggaagtagc 7140 aattgggagt tgcatacagt tacttcgtca gagaaaggag cgcccagtat gacaggcccc 7200 cacccctgat ccggccactg tgcacaggtc gctgagggtg tgagaacacc tctgcagggg 7260 ctccggcaca tgtgggtttc atcgtctcac actccttcag gctgcagggg ttgagtgcag 7320 aaagggcaag cttcatctcc atggtgcctc tccaggctgg caactctggt cggcctctgt 7380 tctttggaca gagagggtgt aggttacagg gtcagtaggg atgctttctg gatcaaagaa 7440 agtgggtgca gtgcttagtc tgttgtgtgg aagagggcac ctcctgggct ttcgtggctg 7500 gagactgtct accaacattc cttccttcaa actagacaaa ccctcctctg ccacccccag 7560 caaattctca gaggtttcca agctgtagaa aaaggaagga aggaaggacg gcattcacat 7620 agctttactt tccgcttcaa aatgtcttaa gtagcatatg ttgttttact gcttttaact 7680 ttggtgagtt ctaatttcag aacgttttgt tcactgagca aaaaaacaga tgaaacaacc 7740 acaggccagg acttcaagtg aggaggacgc ctttgtttgc cgtggttggt gggagcacac 7800 gccggagccc ggtaacgtgc ctgtgggagt gaccaagggc cacccgccca agggaaaatg 7860 ttcattcttc atcagctttg ctaattctgc tttgaggcag taaaatgcaa aagaccatag 7920 aatttgtatt tcttttttta aaatacaatt tataacatta tattttgtac tctttatatt 7980 agaatttgta actagattga tgtatttaac tatttctgaa aaagtaattc aatgttttag 8040 ttgtgtgata aaaatattta gataaaacat attcattcta ttggaatttg aaataaataa 8100 aaacatcttg gagttctgaa aaaaaaaaaa aaaaaaagat ctttaattaa gcggca 8156 94 668 DNA Homo sapien 94 tggtcgcggc cgaggtatcc cttagaaatt gacagcttct atgaaattta caatcaagaa 60 ggcataagaa caactgctgc agcttcagaa ctatgcagaa aataaaatgt caacagctgg 120 gagaaaaaat tctcagtgag caacagagcc agtgaaaaat atcaccagta gagcaggcac 180 ctgagacagg gaaatggcac ccactaagtg caggtctaca ggggctgacc ttgcagacca 240 tttatggatc ccaagttacc aaaaccctta tttgattatg aactgcatag tagataccaa 300 tacatcagag cattgtctca atgttaatat ctatctgtgc tgattgtatt gtggtcatgt 360 aacagaatga atgcccttgt tcttaagtga tacgtgggaa aatatttgag gggtgaagtg 420 tcatgatgtt tgctacttac tctcacatgc tttggcaaaa ataaaacatc tctctctctc 480 caggcaaaat atagtaatca gtaaaatatt aacaatctgt aaaaccacac cacaaccaaa 540 caaaaaaggt tgggggacaa ccaagggcaa aagggtgttc ccggggtgaa atttgttttc 600 gggccaaaat tcccccacat ctcccgcaca aagcgggagc aaaaaaaacc acaaaaaaca 660 cacataca 668 95 746 DNA Homo sapien 95 gactaagaca cctttctaga cagagaggag gccgatggca gacattctca gataggtttg 60 tagctattga cctggctgca tcaaaggaga tgaaatccct tagaaattga cagcttctat 120 gaaatttaca atcaagaagg cataagaaca actgctgcag cttcagaact atgcagaaaa 180 taaaatgtca acagctggga gaaaaaattc tcagtgagca acagagccag tgaaaaatat 240 caccagtaga gcaggcacct gagacaggga aatggcaccc actaagtgca ggtctacagg 300 ggctgacctt gcagaccatt tatggatccc aagttaccaa aacccttatt tgattatgaa 360 ctgcatagta gataccaata catcagagca ttgtctcaat gttaatatct atctgtgctg 420 attgtattgt ggtcatgtaa cagaatgaat gcccttgttc ttaagtgata cgtgggaaaa 480 tatttgaggg gtgaagtgtc atgatgtttg ctacttactc tcacatgctt tggcaaaaat 540 aaaacatctc tctctctcca ggcaaaatat agtaatcagt aaaatattaa caatctgtaa 600 aaccacacca caaccaaaca aaaaaggttg ggggacaacc aagggcaaaa gggtgttccc 660 ggggtgaaat ttgttttcgg gccaaaattc ccccacatct cccgcacaaa gcgggagcaa 720 aaaaaaccac aaaaaacaca cataca 746 96 978 DNA Homo sapien 96 cggccgaggt accctgtgcc aactagggga ggagaactgt tgcctgctaa gttggtggca 60 ggaaccagct tcctgaagga tataaattcg ctggaagaaa gaccttggtt tatgttccag 120 tgctgttttc ccatctctag agcagtggct ggcagacatg tggctactca agaatggttc 180 ccagatgaat gaatgcagga aacagttccc tcctccaatg agattaacag ctgatccatg 240 cttataatga ctgaactctg taaagagggg aaccctctgc caatggggga tcaaaatggt 300 taatgagagc cctgctgtgg agagaggtag gacagcaagc acagaagcac ctgaccccat 360 gcagaggacg ggaggcagaa gcaggggcca gactggaggg agtgatctcc atatgcccat 420 atagcatcca tctgtcttgc caagcaccct tctggggtcc tctaccttta ccagagcata 480 gtctcttgtg cagatcaatg aaacgaagcg aagctggata gactatggcg agagcacttc 540 cctctctgcc tcccccaaga tgaatggcta cttgtggaga ggagctgtgg catataaaca 600 ctttcatcct tacccaaggt cccacatctc cctcaaatgg cataacaggc agacgagcgg 660 ccaaccaact ccctctgatt ctcatacaca gggtgtggcc ttccattggc atctttgagt 720 ggccccaagt cgtacgcaga ttgtggactc agtacacagc ttgcgcaaac ctggacaatg 780 tggccatggc ccatcataca cctctacacc acctcatagc gacgttgaat atgagatcca 840 cccgtagtgc ccagctcata acatcctctc cattaagatt gaccacaggc aacttaccat 900 tgactaggac caagtccccc aaacaccaaa attgagaaca gagcaacatg gtgccaaaca 960 tatcacagag aaatcaac 978 97 787 DNA Homo sapien 97 acctggcaca aagcaaacaa taaatattat tgttattgtt gttataattg taaaatgaat 60 gacttcaaaa acatagtccc agtttggagg gattttgtga tgcagaatat ctaagtcata 120 gaaatagaag acaggtggaa taagtatatg ttcagagttt ttagatgtgt tgagtagaga 180 cggtaataat ggaagcatta aatacaaatg aaaatcacac cagatatccc tgaaattcaa 240 gcaaagaaag ttcatcatgt attcttgggc agcaagagaa aggactaggg ttatggcaat 300 gtgtggaaaa gttgaggctt gctaagggtt gagatctgtt ggtagccctg gatcacatgg 360 ggtcagcacc aggcagtgcc tctgaaagcg gagagaggtc ctggacttcc cttgtgtata 420 acagttccta gtgtccaaca atgaggaaac ggtgaagcat ggttacaaaa ctgtgacaaa 480 acatatttac atctagcact gttaccactc accatgccaa acattggctg cacacgtgca 540 gcccttattt gtaattaaca tcaaaagact agatctgaag ccttccataa atgagagacc 600 attcatatgg cattcctgga acaaaacact gcacaggtac caaggctctc cactccctga 660 cgggttggtg ctgaacagtc agggattgtc ttgactagac ttctgatgct tctgcatctt 720 ctttcctctt cccggaattc caaataacca attcatacca ttgtatttat gcttcgggta 780 acctagt 787 98 3670 DNA Homo sapien misc_feature (3416)..(3416) a, c, g or t 98 agcggacagc cgctccctcg ctctgctggg gcctccggac gcgcttccca cgcgggtctc 60 tggaacactc ggtccgaacg cacgcctgct tgcactcaca ctgcggttca cacccggagg 120 cgctctcgca ctcacactgc cgctcacgcg cgctcacact cccccacgcg cgctccgctc 180 cggctccagc cccgcgccca gcgaaggcgc aggcactgct gccgagagcg ccgaggggcc 240 ccgcggcctt cccatggcgg acctgagctt catcgaagat accgtcgcct tccccgagaa 300 ggaagaggat gaggaggaag aagaggaggg tgtggagtgg ggctacgagg aaggtgttga 360 gtggggtctg gtgtttcctg atgctaatgg ggaataccag tctcctatta acctaaactc 420 aagagaggct aggtatgacc cctcgctgtt ggatgtccgc ctctccccaa attatgtggt 480 gtgccgagac tgtgaagtca ccaatgatgg acataccatt caggttatcc tgaagtcaaa 540 atcagttctt tcgggaggac cattgcctca agggcatgaa tttgaactgt acgaagtgag 600 atttcactgg ggaagagaaa accagcgtgg ttctgagcac acggttaatt tcaaagcttt 660 tcccatggag ctccatctga tccactggaa ctccactctg tttggcagca ttgatgaggc 720 tgtggggaag ccgcacggaa tcgccatcat tgctctgttt gttcagatag gaaaggaaca 780 tgttggcttg aaggctgtga ctgaaatcct ccaagatatt cagtataagg ggaagtccaa 840 aacaatacct tgctttaatc ctaacacttt attaccagac cctctgctgc gggattactg 900 ggtgtatgaa ggctctctca ccatcccacc ttgcagtgaa ggtgtcacct ggatattatt 960 ccgataccct ttaactatat cccagctaca gatagaagaa tttcgaaggc tgaggacaca 1020 tgttaagggg gcagaacttg tggaaggctg tgatgggatt ttgggagaca actttcggcc 1080 cactcagcct cttagtgaca gagtcattag agctgcattt cagtagccaa agaggacagg 1140 aacaagtctg tcttcatgag ggaggaagac aatggtccta taatgccctt ggataagaaa 1200 aggaaacttt tgagctgcac cttcagttta tcctcaaagc ctgcgttgtt tgtcttcatc 1260 taatccagct ttgatggaca tctgtgatgg ttgcctgtac acttgctgaa atgaaatatt 1320 agaaatggct gtatattcca aagaaaccct atattatata tccacattac tgctgctagg 1380 attcatagtt gcacatactg tttattgctt atgtgtagaa ggaatgaaac tagtttccag 1440 agttgttatt aatatgaata tatatcatgt gttaatattg agaaaggaaa aatacattcc 1500 cggtgttagt agttcttcat ttcctgtctc caacagaaaa ttcactcatt ttagaactag 1560 tgtaattctt gataataaaa taagagtttt gattaagaac agcatagagc ttcaaaatgc 1620 aaagtgaatg attagtaaaa ttatgtctca ttttattttt tcagcaccca taccacaatt 1680 aatattaggc tggattgcca tgggaaacat tttttggcat taatgcagca acataatact 1740 cactttaggt attactacat agttgaagga tttaactgaa tgtatggatc aaatttattt 1800 atttgacata ttcgaagctg tggtttaata ggaatttgag aaaggtgtaa gaaataggat 1860 aaaaagaagg tcagcaccat gtaccaggaa tagctttact ttccatacat agaaatataa 1920 atttagtggt atcctatatt actttagtgt cgtacgcttt gtaagactta aatattttat 1980 tctattgatt ccactacttt ggtatgttaa gacatttctt taaagatgac caacaatatc 2040 cttattttag gtgccactag cagatgtaag cgtatactta gttgccgtta gatgtgacag 2100 aatgagataa tttatgtaaa gcagtagagt acctggcaca aagcaaacaa taaatattat 2160 tgttattgtt gttataattg taaaatgaat gacttcaaaa acatagtccc agtttggagg 2220 gatttgtgat gcagaatatc taagtcatag aaatagaaga caggtggaat aagtatatgt 2280 tcagagtttt tagatgtgtt gagtagagac ggtaataatg gaagcattaa atacaaatga 2340 aaatcacacc agatatccct gaaattcaag caaagaaagt tcatcatgta ttcttgggca 2400 gcaagagaaa ggactagggt tatggcaatg tgtggaaaag ttgaggcttg ctaagggttg 2460 agatctgttg gtagccctgg atcacatggg gtcagcacca ggcagtgcct ctgaaagcgg 2520 agagaggtcc tggacttccc ttgtgtataa cagttcctag tgtccaacaa tgaggaaacg 2580 gtgaagcatg gttacaaaac tgtgacaaaa atatttacat ctagcactgt taccactcac 2640 atgccaaaca ttggctgcac acgtgcagcc ttatttgtaa ttaacatcaa aagactagat 2700 ctgaagcctt ccataaatga gaggccattc atatggcatt cctggaacaa aacactgcac 2760 aggtaccagc ctctccactc ctgaccgggt tggtgctgaa cagtcaggga ttgttcttga 2820 actagacttc tgatgcttct tgcaatcttc tttcatcttt ccctgaaata cacaaaataa 2880 acaaatacaa taacaaatag taattaaatg actttcagga taacatctag ttgttcagac 2940 ttcacccttc acaggtgtgt gtgtatgtgt gtttatgtct gtatattgaa gcaatttgaa 3000 tttatttact gtatattttc tgagtaaaag actgaaatga actacttggt tcagatcatg 3060 gtgtccattg gtgacattgt ttggaggcat aatattcttt atatggaaaa tcctttaatt 3120 ccacagttag ttacctcaga ttcagaatat gaatactgtt tataatacgc ttttgtagga 3180 atgaattcga aaggtagttg tcagtaaaca aaagcacaac aaactaatct cagagtctgc 3240 cctgatggct gtgataggga cagaaagcta aaccctactg ctgacgcgcc ccgcacattg 3300 ggcgcagaat ttcccaagaa aacggggcaa atcaccgcca cggtcctaac tctgaactct 3360 atacgggcca tctcgcctaa accactacaa ggcacgcacg ggaaaggact ctccgntcgc 3420 gactcgcaag cctacggccc ccgaacgaca ggcgcaccac gacaccaccg gcgcgtctac 3480 gagacatgat cagcgtcaag ggcacctgaa aaaacgatgc cccaactagt gcggcccgca 3540 accaggcaga cactaagctt gatagcacag cgactgcacc aagagctaat cacgcacaca 3600 accaaagaca gaaactaccc actctatcac tacacggacg acactagaaa caacctgcaa 3660 ttgttactgc 3670 99 938 DNA Homo sapien 99 ccacccccga cgacgacata ttaggggaac gggccactag atggctggtc gagcggcgca 60 gtgtgatgga tgcccgggca ggtacataat gttcagacct cctccatcct tttaaatgcc 120 tgctgcagta aataactagt ttgagtagaa ctagatcctg tctatctatt tggcacatgt 180 tctgctgcct ggggagtaag caagctaaag ggatgagaaa gaccacctcc ccctaccctg 240 gaaattgcac tgcaaggcag ggcgagaatg gggtagctgg cagacctggc ctccttgttc 300 ccagtcttag ttatttcttg cagagattca gtattcagta aagaatagca ttcaattagt 360 caaaaaatat atatctaact tcttcctttc ccttcccatg aatcattgca cgtcattccc 420 taagctttct tctctttcca cctcatggcc tgctcagtct tcccatccct accaatcaca 480 gactctcagc ctatagacgc agtcacagta tctcaactca tccgcctctg cttcacacta 540 cattaacaat acctcctcac tcacatacta cataactcca gctctagtct tccaaaattc 600 acctttcatg atgccactca gcatctcaaa tacctttcat gggctctctg ctgccaaagg 660 ataacaggtc aaagtcatta gcctcaacag tgggcttcaa ccagccttgg gacctcagcc 720 catttatcca tcacagaggc tggtaactag tctcactgct caggctgtga gtgttcctga 780 tccttgtgac attctgtgct gtgctttaca tggaacaggt ctttcctctc tctggcccat 840 tcgaatcctc taatcaagcc catctgattc tgtacagaac acattttcaa gttcaattcc 900 ctggatgcgg ttgcgcgaaa agttgcttaa tgactggg 938 100 376 DNA Homo sapien 100 tactcttggt tttcttcctc caagactact ccttactcat atcagcaaat agcagctctt 60 ttcaagtgct cagtgtaaaa acctacaatt aatccttgat ttctctttca gtcagcctat 120 actaaatcaa tttcatttaa aatatctcgg ctactactct gcatctccac tgctaccatc 180 ggcctctcca gtcacattct ccaagagcac tctatctcat ttaaaagaca aaatctctgc 240 agtggcctgt gatgctcctt aatggcctac ataatccagc cctcaagcac ctccgtgatc 300 tctgtaaaac tttcccttgg tcactgtgct tcagccacat taaccagctt gcatatttct 360 cacattcacc aagctt 376 101 3661 DNA Homo sapien 101 ggacacaact caacccagta acagttagtc aatggctgtg gcaggctaaa tgtggctccc 60 aaatatgtcc atatcctaat ccctacagcc tgtgaatatt accttatata gccaagagga 120 ttttgcagat gtgattctga gattgagaga ttatgccaga ttatccaggt aggccccaaa 180 tgtaatcacc acagtcctta taggagaggc aagaaagtca agtgtagaag gaggcgatag 240 aaggagagag ggatttgaag attaataggc tgcttgcttt gaagacagag ggaagggacc 300 atcaaccaga aataaacctc tagaagctgg aaaaggcatg gaaatagacc ctcccttaag 360 gtctctggag ggagtgcagc tttgatttct accgagtaaa attgattttg tacttcagac 420 ctccaaaact gtaagagaat gactgttgtt ttaaaaccat tgagtttgta gtaatttgtt 480 gcagcagcca caagaaactg gtacaacatc tatatagaat tttttcagat aattgggagg 540 aaatttgaat atggatggca tattaatatt actgaatcag cattaaattt gttaggtgta 600 ataatgtgat tgtagctatt taggagaata tcctattttt aagagacatg ccaccatatt 660 tagggagaag tgccaacata tttgcagttt attttcaaat ggttcagagg ctgtctgtgt 720 acatgagaag acaaagataa ggcaaatgca gcaaaattgt aataattggt gaatccaggt 780 gaagggacta tggctggtct ttgtactttt ttttccaact tttctgtagg tttaaaattt 840 tcaaaataaa aaatgggaaa tactttaaaa attgtaatca aagacattag tacagaaact 900 ttcataatgt attttatttt tacagtaaaa ttaatttatg taaattgata gaattttact 960 aatttcactc ccaagttaca ttaaaaggct tacatatgtt tgataatagc atatgtaaac 1020 tagaactctg aatgatatcc attggtcata atacgtacta tgtagcggta atggtgactt 1080 ttgtgattgc acaagtctag agatgcccca aatgacattg acttagacat ctggttattc 1140 taaggctgaa actgaagttg aatagaaggt tttagtcaaa tactgagatg aaaactgagg 1200 cagtcctggc gggggggagt gagtgtgtgt gtatatatac acacatagac atcatgcttc 1260 taaacattta cagaaagaaa gggtagatta tctacaaaaa aataagaatc agactgatat 1320 gagatcttac aaacctaacc cccttctctt tcctaaactc cagattctca tatttctgac 1380 ttcctatttg atatttacac ttcgatattt accaggagtc ttcaacattt tgttcaaaac 1440 agtactcttg gttttcttcc tccaagacta ctccttactc atatcagcaa atagcagctc 1500 ttttcaagtg ctcagtgtaa aaacctacaa ttaatccttg atttctcttt cagtcagcct 1560 atactaaatc aatttcattt aaaatatctc ggctactact ctgcatctcc actgctacca 1620 tcggcctctc cagtcacatt ctccaagagc actctatctc atttaaaaga caaaatctct 1680 gcagtggcct gtgatgctcc ttaatggcct acataatcca gccctcaagc acctccgtga 1740 tctctgtaaa actttccctt ggtcactgtg cttcagccac attaaccagc ttgcatattt 1800 ctcacattca ccaagcttgt tcctgccttg gggcctttgt acttaccatg ttctgttctg 1860 agaatactct gcctcaagat atcctacaac tatcttactg tattcagctc tctgctcaag 1920 tattaactga tgaaacctgt catccctact ccactccatg ttctgcttta cttaacagca 1980 attgcacata tggccccctg aataatatac atttagtcac ttatttttac ttatctgcta 2040 attaaaatgt agactttttc tattctgttt actgctgtat tcccagcatg ttttatccga 2100 atgtgcagtg gtttcttttc ttctccctta tcgtgggaag tgatgtgcac aaatacacat 2160 aatggagcct gaatgtcata ttgctttcat acctgtgtga attttggtaa gaaaggaaaa 2220 gtagcgattg acaggtaata taattacatt aagtcactct catagttagc tgtttattgc 2280 tttcctgctc ttattctcag tccccaggac caaatgttga ccactacctt cccccacata 2340 taattaggtt atttaccgaa cgccatgcag gtggctgtta aaaggaagat atatacttac 2400 cttataaact caacttttcc ctgttgtctt tctgtctcac ccctacctcc atgctttaaa 2460 ttaacttttc aggcttaggc cttatctctc agtagagcca tataaggtat gtgtaaaagc 2520 aggaaaatgt ttcctgggga tgaagctttg aaaagctttt tttttttttc ttttggcaat 2580 aaaataaggt agattcagca caatacctaa taactaaaaa atctgttttt aattgggtgg 2640 ggcagacagc aagtgtgtca tcctggaaga tactatttgg gattttatgt aggtacataa 2700 gagaaaaaag tgaacaaaag caaggggcta ccaggacgcc gcagtatgct taacatgtat 2760 tttctaagtt tgtattatgc ctttatcttg gtacttttat cttctgttct cacttgatct 2820 ttttgaaatg tattttaaat cctaataaaa atatataaag tctggaatta ataaaggatt 2880 aaatgaaact tttgtatatc tcactgaaat tctcagaaaa aaggggggtg tggggagggg 2940 gaattgcctg gggtagtgag tgaaaattgt gaccaggttc ttactaagga atatggcaac 3000 tgcataatca aatgtcagtg gttaccaaac ttatgaatca cctggtgttg tgtcatagat 3060 tgtctatcct tgcctctcgc ccccagtgat ttagatcagt ggaactatgt ggggtttaag 3120 aaatatacaa tatatatttg tatatatttg tgtgtctcga aagcttcagg gttaaataag 3180 ttttaactgt ttaggaaaca ctattgtttt aggtatccag tctcaaagac gaaggccttt 3240 aaaacttact taatttttca ttacatttct tgcccagaaa attgtaaaat acccaacgat 3300 aacaatgggg aattgtctat cagcacttga ctaaaaagct ttactatcca tgacagcagc 3360 ctttgcatta ctcaattctg atggcattta acgtcttgaa acccagaaat aaatacctat 3420 agactcacag tacctgaaag gaataccaaa ttgagacaag agagctatat aaaccaaaaa 3480 ttgcttcaac cacagaatgg aggtctacag gtgcggaagg aaagtttata tggtgaggct 3540 tggtcgcaaa actattagga atattttcag gttactacac aattttgcga gctcaatatg 3600 cagttaacac tttttccctc gaatctcctg agcagattta cattgaccgg acccgtagca 3660 t 3661 102 698 DNA Homo sapien 102 acatttccat ttccaccggc ttggagcaga gctgtcgagg agtgctattc taggatcctg 60 atgatgacca caagggcagt ttgtattcag ctgtccctgg gaacacttcc ctgaaagcgc 120 tcagggacat tttcatcagg cacagtgctc caggctacgg cactctgtat tgttccctgg 180 tggctttagg gggctgggca tcgtagctga aataggacaa cagggagatg gctgagtgtg 240 tttcccaact gccagatgac aacaggtcta tcagcataaa gtcatcatat aacttagaag 300 aaaccttacc ctcggtgaaa tctcccagca gatcagcaac gaaatggact aagcaacttc 360 ggtagaaaca catggggcta ggatataaac agttcatagg aaaggacacc tgatatcatt 420 aatgattagg gagagaaatt gggtagctaa cagcaggggt gagagagaaa ctttatagta 480 ttttcctctg tagcttttga attttaagac atatgaatgg attttttttt taattgtaat 540 taaagtataa tttttttaaa agagaaattt ggagtcattt aacttgtaag acaaaggcta 600 tcttgtaata agaatactgt tcttcctatt tgctctagat tttaagtttg gatgggctac 660 atggtttctt agggcagaac cactcttata gactattt 698 103 1217 DNA Homo sapien 103 acatttccat ttccaccggc ttggagcaga gctgtcgagg agtgctattc taggatcctg 60 atgatgacca caagggcagt ttgtattcag ctgtccctgg gaacacttcc ctgaaagcgc 120 tcagggacat tttcatcagg cacagtgctc caggctacgg cactctgtat tgttccctgg 180 tggctttagg gggctgggca tcgtagctga aataggacaa cagggagatg gtgagtgtgt 240 ttcccaactg cagatgacaa caggtctata agcataaagt catcatataa cttaaagaaa 300 ccttaccctc ggtgaaatct cccagcagat cagcaagaaa tagactaaca attcggtaga 360 aaaatggggc taggatataa acagttcata ggaaaggaca cctgatatca ttaatgatta 420 gggagagaaa ttgggtagct aacagcaggg gtgagagaga aactttatag tattttcctc 480 tgtagctttt gaattttaag acatatgaat ggattttttt tttaattgta attaaagtat 540 aattttttta aaagagaaat ttgggagtca tttaacttgt aagacaaagg ctatcttgta 600 ataagaatac tgttcttcct atttgctcta gattttaagt ttggatgggc atacatgggt 660 tttcttaggg cagaacccac tctactagac ctatttaacc ccatgacaga gcctagaagg 720 aacaggtgta atagaagatg gcatttatgg caagaaggtt gatcaagttc tccattagaa 780 tttgaaccag atctaatgcc ttttcttccc ttgtttaaga acggcccggg atgttggact 840 tcacgggcaa ggccaagtgg gatgcctgga atgagctgaa agggacttcc aaggaagatg 900 ccatgaaagc ttacatcaac aaagtagaag agctaaagaa aaaatacggg atatgagaga 960 ctggatttgg ttactgtgcc atgtgtttat cctaaactga gacaatgcct tgtttttttc 1020 taataccgtg gatggtggga attcgggaaa ataaccagtt aaaccagcta ctcaaggctg 1080 ctcaccatac ggctctaaca gattaggggc taaaacgatt actgactttc cttgagtagt 1140 ttttatctga aatcaattaa aagtgtattt gttactttaa aaaaaaaaaa aaaaaaaaag 1200 atctttaatt aagcggt 1217 104 193 DNA Homo sapien 104 ccgggcaggt acaatatgga tttcaaaata acgttcactg gtaatccttc ctgatgccaa 60 ttttaaaatg aagaccgtct aaatttttct gaccagttat tagttgccct gcctctcgga 120 aatgtgttta aacttttctt tcaattattt gatacctttt gcccaagaga ttactatctc 180 tctctttttt ttt 193 105 542 DNA Homo sapien 105 ggccgcactt tttttttttt ttttttagtt atatatttaa tgaatcattt ttattgcaaa 60 gggtaaatta catgaaattg acaaaattta gtccatgtaa tatctatcaa aatacataca 120 tgtaagtgtg tgtatattta tatatgtata cagtacagtt ttcacaaaaa gcttcaacat 180 tcctaagaaa cacagacata gtcattctgg tacaatatgg atttaaaata agttcatggt 240 aatccttcct gatgccaatt ttaaaatgaa gaccgtctaa atttttctga ccagttatta 300 gttgccctgc ctctcggaaa tgtgtttaaa cttttctttc aattatttga taccttttgc 360 ccaagagatt actatctctc tctttttttt ttttctttta agacagagtg ttgctctgtc 420 actcaggttg gagtgcagtg gcacaattcc tgatcactgc aacctctgcc tcccaggctc 480 aaacgatcct cccacctcag cctccccagt agctgggacc acaggcacat accaccaagc 540 tt 542 106 715 DNA Homo sapien 106 ccgcccgggc aggtcctaaa tagaattcaa gattagacta aatgattttc agcagagcac 60 attcaaggtt ttacattcta tgattgaaaa aaattttttg aaaacttttt atttcattct 120 ttcctgtagg attttgctac aaataacttt gggaatgaat aaagtggaat ggtaactttc 180 cagtggttca gaattgaatt agacttcttg tgactgtgat gtttggtttc cattgaaata 240 tatgaagtga gatgtcatat cctgaatata gtttgtcttc cccaattact tgatagcatg 300 tctgtcagcc agtaaagatt aagaacagag tttctctaaa ttcctccgat tattccacta 360 aggcacatta aaatacttaa ttttgggaaa ccagacatca cagatttctc catgaagtcc 420 taaatcttct ttaaagtcag aataggtatc ttagttactg acagtattca ggtttttttc 480 tcccttggtg atatgtcatt ccatcagtga aaaaatattt tctcccaagg gatatagaaa 540 ggtattctgg taatacatta tcatcaatcc tttaacagta acagtctggc acttatcaca 600 aaaacgacca tttcttataa ccagaaagat atcttagatg tcttcacata tatttactat 660 gctgtagata aagatgcccg ggttatgggc tccatttcat ggcctgggtt acgtg 715 107 1716 DNA Homo sapien misc_feature (1594)..(1594) a, c, g or t 107 agactgcaat ttctgactaa agcttttaat gccaggttaa acaggagaaa ctttttccac 60 tagaagaaaa tccttgctat ctattttttc caatagaaga aaatcctgct atttatttta 120 tttgatgaat aaacaaattt attgcagtag cttaaaaaaa tttttttttt aaacagtctc 180 actctgtcgc ccaggctgga gtgaagcaat gtgatctcag ctcactgcaa cctccacctc 240 ccgagtagct gggattacag acatgcacca ccaccctcag ctaatttttg tatttttagt 300 ggagacgggg tttcgccatg ttggccaggc tggtctttaa ctcctggcct tacgtgatcc 360 gccccccctt ggccttccaa agtgctggga ttacaggtgt gagccactgc acctggcctg 420 tagtagctta aaattttcct tgagaaaatt cctgacttta aaaataaccc ttatataagt 480 acaagtgatt gtgacaaatg acgtaaaaat ggcattcatg atgtctgaaa caagcctaaa 540 tagaattcaa gattagacta aatgattttc acaaagcaca ttcaaggttt tacattctat 600 gattgaaaaa aattttttga aaacttttta tttcattctt tcctgtagga ttttgctaca 660 aataactttg ggaatgaata aagtggaatg gtaactttcc agtggttcag aattgaatta 720 gacttcttgt gactgtgatg tttggtttcc attgaaatat atgaagtgag atgtcatatc 780 ctgaatatag tttgtcttcc ccaattactt gatagcatgt ctgtcagcca gtaaagatta 840 agaacagagt ttctctaaat tcctccgatt attccactaa ggcacattaa aatacttaat 900 tttgggaaac cagacatcac agatttctcc atgaagtcct aaatcttctt taaagtcaga 960 ataggtatct tagttactga cagtattcag gtttttttct cccttggtga tatgtcattc 1020 catcagtgaa aaaatatttt ctcccaggga taagaaaggt attctggtaa tacattatca 1080 tcaatcctta aacagtaaca gtcttggcac ttatcacaaa accgacccat ttcttataac 1140 cagaaagatt atcttagact gtccttcaca ttatacttta cctactgcct tgtaagaata 1200 agagttgctc actgtgttta cttgctgtcc tccatattct ccattgcacc attggtgtat 1260 aacgttaaga gtttcattga atattatttt aagtattaca aaaggcagct tgcttcttaa 1320 tctatgcatc tttggggttt ttgaagaaat ttaattcttt gatgtaaaaa ggaactgtta 1380 aaaaagttgg aagctctgca cctgtgtata tatatatttt agcaataaag cagcatgggc 1440 tgagaatgca ctgaaaaaaa aaaatgctag tgacttcagc aagtcataat cttcctgcgg 1500 gtggagggtc tcactgcgat gtggatggcc gctggggctg accagggtgg tggtggcaga 1560 aggctggggc ggctgtggca gtttcttaaa atangacaac aatgacattt gccacattga 1620 tagacttttc ttttcacaaa agaagtctct gtagcacgtg gttgctgttg gtgcacttta 1680 cccacagtgg aacttctttc aaatagtctc aatcct 1716 108 666 DNA Homo sapien 108 tcgcggccga ggtacttaat aatgactgaa tttcatgttc ctacagtcat acatattcat 60 tagaagtttt atgttgttgg tctgatctga ttcttctttg tttgtgggtg gaacggcact 120 gagagaagta tagtttttta aacttgaaca tgttcagtag ttacattgcc ttagaaaacc 180 cagacacata gcagtggaaa tgaaagaaat ggcatcagaa gtgacttaat ttagcaattg 240 tgattcctct tgtaaaacaa aacaaaaaaa caatgccata ttttttggag aaaagttggc 300 aatatagggg tttcgttgtc tgtttcacaa gaagactcat ttgttctttt gggggaacca 360 gtgccttaca gattttgtat atactgtaat tattcaggac tagggaacaa acaattgtat 420 tgtatttgtt acagattgta tatggctttg ttttaacatt cccctaaata aaatggcttc 480 attctcccct tggaaaaaaa catgactgtt atgttataaa acaaaaaaaa aaaaaaaaaa 540 aaaaaaggtg ggggtaccgg ggcaaaacgt gtcccggggg gaatggtttc ccggcccaca 600 aatcccccac attgcgagaa aaccgtgcga acaaaaaaaa aaaaaaaacg aaaaaaaaaa 660 acaggg 666 109 1983 DNA Homo sapien 109 gaatttcgta atccttgaaa ttgaaaaaaa aaaaattgtg tttttaaaga gtgaaaacag 60 ttaggaaaca agtagaactg taatcagaac gctgcttcaa ttgatattaa aaataacctc 120 aataataatg taaaggttcc tttctcttgt gtcagttata ttcttaggga tagcctagaa 180 ggaatatatg gttagaacta agtgtgacta atcatctgag ccttgaagag aaacttcagt 240 gcctctaaac agatcatcta caaaacaaca ggtaaacatt tatgccagtt aagtgggtca 300 tgtttttgtt tcttgggttt ttcctaaatt taagtgaggt tgggcttacc ttgtagataa 360 aattatgttt tctttttggt aaatacttga atgtggataa cgtcaaatca gaatattttg 420 tgaggaggtg atgatttgaa attaagctag atttctaggg aggtgttggt tccaatgaag 480 gatgggaaga aattaaaata gtcttcaaac ttcttcctta ttatatttgg ttgctttgga 540 aaagattggt cctatcctca atctaattta ttcactatta atattttaaa aacattcctg 600 agatacttaa aaagacccac ttagcgatta tagttgctca atgaaacaag aatttattta 660 tgcatagatt tttctctgta tcttaccaaa atccacttta cttagataac actaaattgt 720 tcttaaagac tactcatttc ccaataatcc tttatgattt caaaatttct agtggctcag 780 aagtgaattt tattttattt gtctttcact tgaataaatg agaacccaga aattaataat 840 gttgtttatt gcttactgtc aggactattt caaagactaa gaagagtttc ttctaacccc 900 tccctctcaa aggaatccta aattattagt tgttagataa gttttgtatg ctaagatatt 960 caggtttata gtttatgtat gtgtgtatat atataaatat atatgtatat ataaatatta 1020 tgttcagttt ggagtctggc acaactccat tatgtggatt agagagtaag atattatgga 1080 tgataaagta ctaaatgaaa cataatattt atttataaaa gtgtgtagat tgttaaatca 1140 caaaaagagt gctatgacca ttatgtatga ggaaacaggc ctttgacctc ctggaaagca 1200 ctgctcaaaa gtcattagtg cccatttttg aattccccaa acagaaagct tcttagaaaa 1260 cacgctgaga ttttatttac agggaattct ttgacacatt tcaattggtg tgtagtcaag 1320 tatagcaagt acttaataat gactgaattt catgttccta cagtcataca tattcattag 1380 aagttttatg ttgttggtct gatctgattc ttctttgttt gtgggtggaa cggcactgag 1440 agaagtatag ttttttaaac ttgaacatgt tcagtagtta cattgcctta gaaaacccag 1500 acacatagca gtggaaatga aagaaatggc atcagaagtg acttaattta gcaattgtga 1560 ttcctcttgt aaaacaaaac aaaaaaacaa tgccatattt tttggagaaa agttggcaat 1620 ataggggttt cgttgtctgt ttcacaagaa gactcatttg ttcttttggg ggaaccagtg 1680 ccttacagat tttgtatata ctgtaattat tcaggactag ggaacaaaca attgtattgt 1740 atttgttaca gattgtatat ggctttgttt taacattccc ctaaataaaa tggcttcatt 1800 ctccccttgg aaaaaaacat gactgttatg ttataaaaca aaaaaaaaaa aaaaaaaaaa 1860 aaaggtgggg gtaccggggc aaaacgtgtc ccggggggaa tggtttcccg gcccacaaat 1920 cccccacatt gcgagaaaac cgtgcgaaca aaaaaaaaaa aaaaacgaaa aaaaaaaaca 1980 ggg 1983 110 758 DNA Homo sapien 110 aaaaaaaacc acaaacaaga gaggattgat tgataatatg gggcatgctt aatctaatca 60 tgctcgagcg gcgcagtagt gatggatcga gcggccgccg ggcaggtacc taacatatag 120 tagacagtgg agagtggttc tctttcgttg tctcaggggc agacagatgg ggtgctggag 180 tcctctatca aagagtcaga gctctatccc agatgtgtaa tgaacgtggt cacagacata 240 ttgtcccatt accatttacc ttccctataa ccactgtgcc tccagccttg tagaatagac 300 acataggagc gcagcaatac gtctaaaaat aggagtgaga gagggcaggg catgcccgtt 360 cttgtggtag aagaaaagaa tgtcaaagaa agcagctggg actaatgaac tttacattag 420 ccatattcca ttatttcagc ttaagtcaaa tgtcggtcct catgaggcaa ctggctttga 480 caggagctac gctaatgtgc cacttaccaa cctttaattt ctgggtaaaa gcagaaagag 540 aaaaactaat ggatttttca ttttccagaa gagacaagaa tcaactacac tagtagtctg 600 tcagaacaaa agaaaacctg catccaatta caagaattat tactgtctct ttaataaata 660 accacattat taaaaaaaaa aaaaacaaaa aagggttggg ggtaccgggg ccaaggggtc 720 ccggggggaa ttgtttcggt ccatatccat acaaaaaa 758 111 3575 DNA Homo sapien 111 atgaaattac aactcaggat taagagtctc actcaaaacc gcacaactac atggaaactg 60 aacaacctgc tcctgaatga ctactgggta aataagaaaa ttaaggcaga aataaataag 120 ttctttgaaa ccattgagaa caaagacaca atgtaccaga acacagctaa agcagtgttc 180 agagggaaat tcatagcact aaatacccac atcagaaatt gggaaatacc taaaatcaac 240 gtgctaacat cacaattaaa agaactagag aagcgagagc aaacacattc aaaacaagaa 300 ataactaaga tcatagcaga actgaaggag atagagacac aaaaagccct tcaaaaaatc 360 agtgattcca ggagctggtt ttttgaaaag attaacaaaa cagatagact gctagccaga 420 ataataaaga agaaaagaga gaagaatcag atagacacaa taaaaaatga taaaggggat 480 atcaccacta accccacaga aatacaaact gccatcagag aatgctatca acacctctac 540 ataaataaac tagaaaatct agaagaaata ggccgggcgc agtggctcac acctgtaatc 600 ccagcatttt gggaggccaa ggtgggcgga tcacctgagg tcaggagttc gagaccagcc 660 tagccaacat ggtgaaaccc cgtctctact aaaattataa aaaattagcc gggtgtagtg 720 gtacacgcct gtagtcccag ttacttggga ggctgaggca tgagaattgc ttgaacccag 780 gaagtggagg tggaggtgag ccgaaattgt gccactgtac tccagcctgc aacagagtga 840 gacactgtca cacaaaaaag aaagaaatat cacaatatgt cacaataggc cgggcgcagt 900 ggctcacacc tgcagtccca gcactttggg aggccaaggc agatggatca cctgaggtca 960 ggagtttgag accagcctgg ccaacgtgac aaaacccagt ctactaaaaa tacaaaaatt 1020 agccaggcgt gatggtgggc acctgtaatc ccagctactc aggaggctga gacatgagaa 1080 tcgcttgaac ccaggaggtg gagattgcac tgagctgaga tcctgccact gggctccagc 1140 ctgggtgaca gaatgagact ctgtctttaa aaaaaaaaaa aaaaaaaaaa aatcacaata 1200 agtcctaggg taaagatggg ggtacagaaa acaattaaat agaacaaaaa caactgtttc 1260 cttttcctgt gattcaagaa gggcttagat cttctactca gcatcctttt actaatgccc 1320 tccattggct ctcacgccca acatttcctt ttttatagct tattttgtaa tgcctcctta 1380 attatccttt aatagaagcc accgctgata agctacctac actcatacag aagcattaat 1440 ataatgcccc agatgtactg tttcagggca aaaaggaaaa taatttccaa caaagtggtg 1500 tgtgtctcac tgtcagatgc ttgcacttac acacggaatc gctgtgcatc cgacagaggc 1560 tgattggcac atggggcacg gggattgtca gctcaaacac cgtcagcagc gttgcccttg 1620 gaaatgggat ttcccagaac agtaaacgtg tctgtccttg atttacagag tagctacatt 1680 cctaggaaat ccagggtaca ttaaaactca ccatgttacc caggctggtc tcgaactcca 1740 ggcctcaagc aatcctccca catcagcttc ccagaatttt gggattacag gcatgagcca 1800 ccacacccag ccagaatatt ttatttctgt tagacacaga gcgttcgttg actcgtctgg 1860 gcgttagtgt taatattctg tacttgaagc aagcccacca agcggctgaa ctgggtggat 1920 aatggaaaat gtcctgtgga tttgggagtg agacaaaccg gcttgagtct aacctctcag 1980 ttagtctaag gctccaagct tgaaagggtt aaatgaagta ctatatttgt tttgtttcgt 2040 tttcgttttg tttgaggctt tgctctgttg cccaggctgg agtgtagtgg cacaatctct 2100 gctcactgca acctccatct cccaggttca ggcgattctc ttgcctcagc ctccagagta 2160 gctgggatta caggtgcccg ccaccacacc cggctaagtt ttttttggta tttttagtag 2220 acacagggtt tcaccatgtt ggctagactg gtctcgaact cctgacctca agtgatccac 2280 ctgccttggc ctcccaaagt gctgggagta tgggtggtga gccaccacgc ctggcctaaa 2340 tgaagtacca catgaccgac cgaccgacct ggggaacata gcaagacccc atctctacaa 2400 aaatgtaaaa aataaaaatt agccgggtgt agtggtacat gcctgtaatc ctagatactc 2460 gggaggctaa ggcagaagga tcacttgagc ccaggagttc gaggctgcag tgagctgtga 2520 tcgtgccact gcactccatc ctgggtggca gagtgaggcc ctgtctcaaa ataaataatc 2580 cagtcccccc caagaaagga atgaagtgct ataatgagaa aaatcctagt acctaacata 2640 tagtagacag tggagagtgg ttctctttcg tttctcaggg gcagacagat ggggtgctgg 2700 agtcctctat caaagagtca gagctctatc ccagatgtgt aatgaacgtg gtcacagaca 2760 tattgtccca ttaccattta ccttccctat aaccactgtg cctccagcct tgtagaatag 2820 acacatagga gcgcagcaat acgtctaaaa ataggagtga gagagggcag ggcatgcccg 2880 ttcttgtggt agaagaaaag aatgtcaaag aaagcagctg ggactaatga actttacatt 2940 agccatattc cattatttca gcttaagtca aatgtcggtc ctcatgaggc aactggcttt 3000 gacaggagct acgctaatta ccacttacca acctttaatt tctgggtaaa agcaaaagag 3060 aaaaactaat ggatttttca ttttccagag agacaagaat aaaataatag tagtctgtag 3120 aaaaaagaaa acctgcatca attacaagaa ttattaatgt atctttaata aataaccaca 3180 ttatttagct gtttaatttc ctaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 3240 aaaaaaaaca aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aacaaaaaaa 3300 aggagggggg gggggcgaga aaaagagccg aggggggagc acagagcggg ccgccgcgca 3360 catatgaaaa aagcgaccca gaagaagaaa cacaaaacca gcaagcgcaa acagaagaaa 3420 taagaaagag aaaaagttac gagacgaata gaaaggaaat aactacagga ccaacacggg 3480 acaaaccaaa agcaaataaa caaagaaaat aagacagaca caagatgcca acgagctaac 3540 gcccggacaa tggaaacagg taaacaacat aaagc 3575 112 442 DNA Homo sapien 112 actgagcagc tacggaagtg caaggcactg taggagtagg gtgagtatac tccccacaag 60 ggctcagggt caggcagggg acggtagaga taaaaaccca cagaccatac acatagctgg 120 cactgtctct gagggttttg tgaggcacac aaatgcttag gagactagac gaagtaagac 180 aatgtctttg acatgaggca gaaatcaacg gaaagcatgc gcttttagaa catgtgtggg 240 actgtttttt ggtatcagca gactgaagag gctttttaaa cgtggaggga aggcaaactg 300 aggcatagag atgccaatac caggtcttgt caggaagaac agagtccaat ttggctgcag 360 gatagggcat atgtagggga ggggataaga ctggcatggg ggcagagggg gacttgaatg 420 tcaggtgaca gagtcaaagc tt 442 113 412 DNA Homo sapien 113 tgtcatacta taaggcgaac tgggcctcta gatgcaattg ctcgagcggc gcaggtgatg 60 gatgttcgcg gcgaggtatc agaagctgtg atgtctgcct tgtagtcctg tgcttgttac 120 tgtaattttt tttttttttt tacgaagcac gtgactggac taatgtaagg cagatgacgt 180 gatctttaag actgctatat atatcagtct cttactctat aaggttttaa attagaaaag 240 gcttatatgg ttaactacct tagactatat ctacagcagg gtctggtttg ccagaacaag 300 tttaaagtgg ctgtttatta agttggctat tttcagaatt gaaactataa gaccgccatt 360 tgacactgaa acttgcgtga atcctaaatt gcatcaatta tctatttgat aa 412 114 625 DNA Homo sapien 114 gcaacaacaa ctgaatggct gtaatacatt aatgtataca gatgaattga gaagtcttct 60 agtgaaatgg ctcagatctt tgttcttggt ccagtcctgt tcagtttttg atcagtgcct 120 tgcaatatca cttgatcgac tcacttaaca tttatacaag agtgcagagg cctcctcaga 180 gaatggatgg tagaaatgca ttgatgagag aacgtttatc tatctatctg tctatctatc 240 tatctatcta tctgtctcta tctaagaagt cataaaggct gagtctaata aggcaaaaaa 300 aaaaagaaaa aaaaaaaaag ctgtggcgat acccagggcc aaagcgtgat cccggcgcca 360 actgcgaaat ccgctcacaa tcccaacaac acccccacaa cccccccccc agccccaaca 420 ccaacacctc aacaaaacct cacaacaccc ccaccacccc acacagccac ccccctacca 480 cacaaccaca tcacaccacc accgccccac ccacaccaca caccccacac acactccgaa 540 caccaccgcc cactccacac acccaccaac caccagcacc aacacaccca cacacccaca 600 ccgccacccc cacaccacac gcagc 625 115 378 DNA Homo sapien 115 gcggcgcccg ggcaggtaca tagtgcagat gcagtatata atttcaggct aggaaaatta 60 gctactagta tgtatctgac agttcctaat agctaagagg cctaagaatg cagacgggga 120 gaaaaaaaac caaaaccaaa aaaaaagaca cctctccaat tgctgggagg gcctgggaat 180 aggtgaagat caaaccacag tgggagagga gggtaaagat gtgagcttca agcgggtaat 240 gggcaagcca cacctcccag ttcctaggag ggaatcgcca cggccgactt cagcattctc 300 gtctttacta agacttaccc atagagaact acagcaggaa accgatttct tcattcattc 360 tctttaaaaa gtatgaat 378 116 8905 DNA Homo sapien 116 atggcggcgg cgctggggcc cccagaagtg atcgctcagc tggagaacgc ggctaaagtt 60 ctgatggtga ggacgccgcg cccctcagac cccgggattc gcgggccccc ggtcggccct 120 gccactccag gccttgctgc tcgctgggct ggcgactggc aagggcctgc agggagcctg 180 gaagtggagg aggaggtggc ggtggcgtgg cgcaggattc ttcagcctac tttcctcctg 240 ccgtcgtccc ctccttccag gagctgtccc cttcccctgg ctgcccagca ccccagtcgg 300 gcgtgggaat atagtggtgt agcaaagaga atttcttcac cttacaccct gccccacaga 360 ctgggtcgca gagcaaggcg ccgggaagga gttggggtta tccccgcagg gcttcgggcc 420 tctcatatac tagtccttct gtctggaatg cttttcttcc ctgtcacttc atccttcagt 480 tctctcagta gtcagtttct cagggaagcc ttccttagcc tgcctgaaag tataccctgg 540 gtgatagatt ggattggatt ggattggatc ggatcggatc ggatcggatt ggattatatt 600 gtatttattt ttaagagaca gggcagctgt caaaatggaa gttcagggtc actagaggtt 660 ggcacatgtc tccagggtaa acacatgagt gcttgcattc atctttggat ccctgcgttc 720 gcttctgttt tagcttttga tgattcctta atttcttctg ccacagccat aatggaagca 780 gttgtccgag agtggattct cttggaaaaa ggtagcatcg agtctctgcg aacattcctt 840 ttaacctatg tcttacaaag gcccaacctt caaaagtatg ttcgggaaca gattctacta 900 gcagtagcag taattgtaaa aagaggatca ttagataaat caattgactg caaaagcatt 960 tttcatgaag tcagccagtt gattagtagt ggcaatccca ctgtgcaaac tctggcctgt 1020 tctattctga ctgcgctatt gagtgaattt tcaagttcaa gtaaaactag caacattgga 1080 ttgagcatgg aattccatgg taactgcaaa aagagttttt caggaagaag accttcgtca 1140 gatcttcatg ttaactgttg aagttctgca ggagttcagc aggcgggaaa acctcaatgc 1200 tcagatgtct tcagtatttc agcgttacct tgcactcgcc aatcaagtct tgagctggaa 1260 ctttcttcct ccaaatttgg gcagacatta tatagctatg tttgaatcct cgcaaaatgt 1320 gctgttgaag ccaacagagt cctgcgggag actcttctgg acagcagagt tatggagctt 1380 ttcttcacag tacatcgaaa aatccgagaa gcattcagat atggcaccaa gattctctgc 1440 agtgccttgc ccagttagct tctcttcatg gacccatctt cccagatgaa ggatcacaag 1500 ttgattatct agcacacttc attgagggat tactgaatac tatcaatgga attgaaatag 1560 aagattctga agctgtgggg atctccagca ttatcagcaa cctgataacc gtgttcccac 1620 gaaatgtttt aactgccatt ccaagtgaac ttttctcctc ctttgttaac tgcctcacac 1680 acctcacttg ttcttttggg cgaagtgctg cattggaaga agtgcttgat aaagatgaca 1740 tggtatacat ggaagcatat gataaattgt tggagtcctg gttaactttg gttcaagatg 1800 acaaacattt ccataaaggc ttttttaccc aacatgcagt tcaagttttc aattcctata 1860 ttcagtgcca cctagctgct ccagatggca caagaaattt gactgccaat ggtgtggcct 1920 ctcgtgagga ggaagaaata agtgaacttc aagaggatga tcgagaccag ttttctgatc 1980 aactggccag tgtaggaatg ctaggaagaa ttgctgcaga acactgtata cctcttctga 2040 caagtttatt agaagaaaga gtaacaagac tccatggtca gttacaacga catcagcaac 2100 agttacttgc ttcaccgggt tcaagcactg ttgacaacaa aatgcttgat gatctctatg 2160 aagatattca ctggcttatt ttagttacag gctacctctt agctgatgat actcagggag 2220 agactccgct aatacctcca gaaataatgg aatattccat taagcattca tctgaagttg 2280 acattaatac aacacttcaa attttgggat ctccaggaga aaaggcttct tccatcccag 2340 ggtacaacag aacagattct gtgattaggc tgttgtctgc cattctcaga gtttcagaag 2400 ttgaatctcg agcaataaga gcagatctca ctcatctact aagtccccag atgggcaaag 2460 atattgtttg gtttttaaaa cgctgggcaa agacttatct cctggtggat gaaaaactgt 2520 atgatcagat aagtctgcca ttcagtacag cgttcggagc agatacagag ggttctcagt 2580 ggataattgg ctacctctta caaaaagtca tcagtaacct ctcagtctgg agtagtgagc 2640 aggaccttgc aaatgacact gtgcagctcc ttgtcacttt ggtggaaaga agagaaaggg 2700 caaacttagt aattcaatgt gagaactggt ggaatttagc taagcagttt gcaagccgaa 2760 gcccacctct taatttcttg tcaagtcctg tgcagaggac attgatgaag gctctagtct 2820 taggaggttt tgcacatatg gacacagaaa ccaaacagca gtattggaca gaggttcttc 2880 agccacttca gcagcgattc ttaagagtga taaaccaaga aaacttccag cagatgtgtc 2940 agcaagagga agtcaagcag gaaatcactg ccacactaga ggccctgtgt ggcattgctg 3000 aggctaccca gattgacaac gtagcaatcc tgtttaattt tttaatggac ttccttacca 3060 attgcattgg attgatggaa gtttacaaga ataccccaga gactgtcaat ctcattatag 3120 aagtttttgt tgaagttgca cataaacaga tatgctatct tggagagtcc aaagctatga 3180 acttatatga agcctgcctt actttgttgc aagtgtattc taagaataat ttagggcggc 3240 aaagaataga tgttacagca gaagaagagc aataccaaga cctgcttctc attatggaac 3300 ttcttactaa cctgctgtca aaagaattca tagatttcag tgatacagat gaagtgttta 3360 gaggacatga gccaggtcaa gcagcaaaca gatctgtgtc agcagcggat gttgtgttgt 3420 atggagtaaa cctaattctg cccttgatgt cacaggatct cttgaagttt ccaacccttt 3480 gtaatcagta ctacaaatta atcacattta tctgtgagat ttttcctgaa aaaataccac 3540 agcttcctga ggatctgttt aaaagtctga tgtactccct agaattagga atgacatcaa 3600 tgagttcgga ggtttgccag ctttgcctgg aggccttgac accgttagct gaacagtgtg 3660 caaaagcaca agaaacagac tcaccacttt ttctagcaac acggcacttt cttaagctgg 3720 tttttgatat gctggttttg caaaagcaca acacagagat gaccactgcg gctggcgaag 3780 ctttctacac gttggtgtgt ttgcaccagg ctgaatattc tgaactggtc gaaacattac 3840 tatcaagtca gcaagaccca gttatttacc agagattagc agatgccttc aacaagctca 3900 ctgcaagcag cactcctcct acgctggatc ggaagcagaa gatggccttc ttaaagagtt 3960 tagaagaatt tatggcaaat gttggtggtc tcctttgtgt aaaataaaca acagaacttt 4020 atgcttaatt tagatccttt ctgcaaagtg cactgaattg ctgaaagttg acttgagtct 4080 tgtcctattc ctcagttcat ttggccattt tggattttgg agagcctgaa actttgatat 4140 gtatgtaata cagtgaaaca ggagaggtca acttggcatc agcttctgct gttaagtgtt 4200 agccacaatc tgtcatatat atgtctttta gattctgaat ggtgatttaa aattttcaaa 4260 atgaaattcc atatatgtgc aaacagatat gggcaccacg aaatacatat gcagtgcctt 4320 ttttcctttt aacataggtg gctagccaaa gtttagaatt tttgtcatta aatatgaaat 4380 ggatatatgc taggcagtgt ttctcaaaat ctccacagat cgcctgcatc acttgaggag 4440 ctggtgaaaa ggcagattct taggcccaac tgtagacctt cagagtcaga atgtctggtt 4500 gttgggccca ggagtcttca tgttaataag cttctccctt tcgtcacccc aaaagttttg 4560 aatcaatgaa agagacattg aaaactctta agaggttttg tgctttctag cttttcctcc 4620 ctttgatgat tgggttttat aattcagcag gaaggggaaa catcatcagg ggtttgttgg 4680 ctttttctta gcttgctttc ttgcttgctt gctttcttgc ttttcttgct ttctgtctct 4740 ctctttcttt tctctctctc tctcacatca acccagtgct gcaggttttg tgtaatacaa 4800 gtcactaatc atactctgat gcctgaactt gaggaggaaa atacatgtat atttttgttc 4860 cgtaaaaata accttaggaa ctgtagccat ttcattgcct taattttaag aggaaaatac 4920 aaaaacagct gatttgtttt agtaagaaac cacgtcttga tgcttcagag ttggtttagg 4980 gtgttagctg ctatgaacct gttgcccctt tcgatcgtgt atttatgtag gtttatcagt 5040 gaaatgaaag gcttgtttcc gtctagtcta actttttgag tgtgtttcta tccagccaca 5100 tagcccatat ctactctaaa tggcttgctt aagcaataat tattttaaag gatgtgaatc 5160 actgattcac acagactatt gcacgttggg gcattagggg caataattct tatccagaca 5220 tgggagccag tgaatttaat ttcagagatt aaaaattcac tttagatcct ctagtttgat 5280 ctcttaatca ggatttttat acagctgcca ggctccccta attcagtgtg ccagcttaca 5340 atgtggaaat gaaagctaat ttatacacag caggcatatg aaactccact cattgcagta 5400 ctttcacagc acagtgacag gtagaggact ctggcacagg tgcactcatg aaactctgct 5460 tccaccatgt tcctgacacc tatctattaa accattctgc aaatacggtt tttctacctg 5520 attgcatata gcatatgtgt cattacatgt gatgctgtgc aaaactttgt ataattctgt 5580 gttattaaca gttaacaaaa ctggagcatc tgaattacat ccaacctgtg catgtgatgt 5640 taggtagatg tgaatgcagg gccttgggcc ataacttaca tttctctcaa tttgattagc 5700 tttgagtcac aattaagggg aagcaaaaac atcttgaaaa gactgctagg aaggaaatta 5760 atatcagtca tccagaagta cacgtttctg tattttaaaa aatactttga tgcatttatt 5820 tttaggtgtt ttttttttcc ccttaaaaaa cttgaagtga tatgcagcag taatctattt 5880 gttttgcatt gttcttggtg ttttgtgttt cccagatccc tcaagctttc tcagctgttg 5940 cgaattatgt gtatctgtgt gtgtgctaag tacagtctct ttaccaaagg gcactgaaac 6000 acacaattga ctggacaggt ccacgcgcca tgacaaaact ataatcaagt tattaaaact 6060 aaagaggagt gggaaaggaa tgccttggta agtaaaaagg catctatatt taataacttt 6120 tatccagatg gcaacatatt tgcaaaattt gcccagatcc tattacaata ctaaaaatag 6180 aaaatttcac ctccatattc ctgaggtgta atttcattag actagtttta gtttaaaaag 6240 accttcttca gattggacca aataatactt ataagatcag cagaatgttg aatattagct 6300 cactggggtg gggagaagcc actaccattt tttaggtgat ggggatgcca ctgagttgca 6360 acggctagac cttttcaggg tggttgtgtc catgtttgcc tgattggatg cttattcact 6420 ttgtgttttc ttttgtttta ttttgtccaa ttttgtcttt agctgtgttt attaacttct 6480 ccggtcttgt tttgttttaa tgctcttggc ccagtgggtg tcaagaacac tggcttaatt 6540 caagtcagtt gatttttttt ctattaaaac tgttgttaaa atatttttta aaacaaaaac 6600 attatttgtg ccctctttta tatatgtcaa agggacactg tcaagtattt catttttaga 6660 tttttgtttt ataaaatttc tgttgttcat atagtatcct ttaacctcta gttttccata 6720 catcctttgt ttgtttctca ttttattttc cttgacccat ttatttccca aggcacaatc 6780 actaaagact ttgtactttc acagtctgtt aatgtggtag cacctgtaac tgtgttcttg 6840 ttctgttaaa aggattgatt tgcttttata gtccttgtgc tggatgagtg gctgcctcag 6900 tagcaaaact acctgacagt atttgacagt gtcctttcca gcaccattat ttgggtcttt 6960 cagggtggcc atctctgtta gaagacagta gcatgttaac atcactgcat tgagtttttg 7020 tctggtgtaa agtatgactt ttaatgtaaa caaactgcag gtttttttca aactaatttt 7080 aagaatttag tcttatttcg ttgtaaactg tgtatctaat tatattacat tactctgttc 7140 agatgggatg gttactacca cttgtccatg attttcattt gaaaagcaag tatctatatc 7200 atttcccccc agtcagcatt atttaacact ccccttaact gtctttgaac tttctctttt 7260 aacaaaaatg tcaagtcttt acagttgtaa tatcaccatg tttcccattt ctgttaatac 7320 ttctatgaac ccctaaagta ttgaagggaa ctagctgtca gtttcaagga ttacaagttt 7380 gagtctccta gtattcaaca tcattctgaa ccctgaaata atatttttct ctgttaaaca 7440 atttttatct gtttgccacc tctgttgtta gaggtggttg tcaattgacc ttactaagtt 7500 agctgtcttt gatgaggaat tattgttatt ggttcctgaa taaaacatta accttttaag 7560 tcagaaggaa cctcggtact tcttaaggtt tgtttgtgtt ttctaaaacc agagaataag 7620 gaactgattt ggctatgagg tttaacatta taattttctg taagctttcc cacaaaaaaa 7680 cattgttgat ttgaggatat aataatgttt taatcttttt aaaatataag tggttattct 7740 ctgacttggt aactatgttc tgaaaacact gcatttaaga atttttaaaa attggttttc 7800 taaaattaaa atgtccaaat taggcatatt gctgagctca aattgatgtg aaatgccatg 7860 gttccagttg aattttaagc atattttcat ttagatataa aatatatgaa gtatgctttg 7920 ttgattatag tgagaaccca tgacatagtt aaccaaagaa tatgtttggt tcaaataaaa 7980 atagaagctt aatactgggc attcatactt tttaaagaga atgaatgaag aaatcggttt 8040 cctgctgtag ttctctatgg gtaagtctta gtaaagacga gaatgctgaa gtcggccgtg 8100 gcgattccct cctaggaact gggaggtgtg gcttgcccat tacccgcttg aagctcacat 8160 ctttaccctc ctctcccact gtggtttgat cttcacctat tcccaggccc tcccagcaat 8220 tggagaggtg tctttttttt ttggttttgg ttttttttct ccccgtctgc attcttaggc 8280 ctcttagcta ttaggaactg tcagatacat actagtagct aattttccta gcctgaaatt 8340 atatactgca tctgcactat gtacctacta gggatctgac ctcaagtgtt ttctgagccc 8400 aggcttcctg gtgtggtgtc ttttaccaca taaaattatt acaaattgca aatgttggta 8460 ttgtgatttg attatctgta caaagaaaga agctctatgc agtgagtttg tggtttaatg 8520 gtcacaaaaa tgttagcact gctaccactc agcacgtgta aaatttttta aatttataaa 8580 tattaaaatt ttaaacttac actaagactt ttcagtttta tttaaagacc cagggatgag 8640 tgtactgttt aaatatttac ctctattaac ataactaatg aaggtataaa attgcattta 8700 gtttttcaga agatgctgca atatgatttt aggaaataag gctatgtatt gagccagtta 8760 taggctgaat atcaggttga taaaatttta tttgtatttt taaaattcat aaatgggagt 8820 taaaatgtgt cttttcacta aatattttta ttacaaaaaa aaaaaaaaaa aaaaaaaaaa 8880 aaaaaaaaaa aaaaaaactg cggcc 8905 117 827 DNA Homo sapien 117 tcgcggccga ggtaccctgc atcactgcca tggttgtgct attctcatct caacatagaa 60 ttggtgggtt ctcctaaggg tgtcaggaac ctctaaaaag atgtgattct ttgggagggg 120 atatttgaaa ttccaacttc cattccccct agcaaaagga agcagctgct gtttaagggt 180 tttatctgag ccactttaaa gatgaatcca tggtattact ctggatacta gccattcctt 240 aggattttaa ggtcacattt tattcctgga tgctttatgt ccccacctcc acctgagccc 300 tcatcctctg ttccctacta tactcccaac ttctactctt tgttttatcc acctatccct 360 attacctgac cctttgtctt ccctgtctcc catccttggg gggacatgca gccctgtggt 420 catggttctg atgacatcat cagggcagcc ctcctgccca ggtattatgg cctgtcagca 480 ttccctgtgc cctccaaacc ttaggcctag aatgcggagc tgccaacata acattcaccc 540 ttttgaacag atggagtcag gcacactaac acagccttct gtcctcaata acacagccat 600 tattgccact tggctcagtc gtcaatgtaa accctcagag tcagctgaac tattttaggc 660 caaacatact gtttttgtaa agtatttttc attaataaat ctataagaca gttctattta 720 aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aggctggggc gaaccggggc caacggctcc 780 cgggggaaat tgtttcccgc caaattcccc caaaaaatgg caaaacg 827 118 6470 DNA Homo sapien 118 ggctccctgg tagctatagc agccgcggcg gttaagtatg cggcgccagg agctgctaaa 60 tgtgaacaat aatgtcttgg aagagaaatt atttttcagg gggtcgtggt agtgtacaag 120 ggatgtttgc acctcgaagc tcaacctcca tagcccccag caaaggcctc agcaatgagc 180 cagggcaaaa cagctgcttc ctcaacagtg ccctgcaggt tttgtggcac ttggatatct 240 tccgacgtag ctttaggcag cttacaactc acaagtgcat gggagattcc tgcatctttt 300 gcgctctcaa gggaatcttt aaccagtttc agtgtagtag tgaaaaagtg cttccatctg 360 acactctccg cagtgctctg gcaaagactt tccaggatga acaacgtttc cagctgggaa 420 ttatggatga tgctgcagag tgctttgaaa acctcctgat gagaattcac ttccacattg 480 ctgatgaaac caaagaggat atatgtactg cccaacactg catttcccat cagaaatttg 540 caatgacatt gtttgagcag tgtgtatgta ctagctgtgg tgccacttct gatccgctgc 600 ctttcatcca gatggtacat tatatctcca ccacttccct ttgcaatcag gctatttgta 660 tgctggaaag acgagagaaa ccttcaccaa gcatgtttgg tgagctgctg cagaatgcca 720 gcaccatggg ggatctgcgg aactgtccaa gcaactgtgg agagaggatc aggattcgcc 780 gtgtgttgat gaatgctcca cagattatca cgattgggct ggtatgggac tcagaccact 840 cagacttagc agaagatgtt atccacagcc tgggaacctg ccttaagctg ggtgatctgt 900 ttttcagagt gacggatgac cgggccaagc aatctgaact gtacttagtt ggaatgatct 960 gttactatgg caaacattat tctacattct tttttcaaac aaagattcgc aaatggatgt 1020 attttgatga tgctcatgtc aaggagattg ggcccaaatg gaaggatgtg gtgaccaaat 1080 gcatcaaggg gcattatcag cccctgctgc tgctttatgc agatccccag ggtaccccag 1140 tttccaccca ggacctgcct ccccaagctg agttccagtc atacagcagg acatgctacg 1200 acagtgaaga ttcaggacac ctgactgata gtgaatgtaa tcagaaacac acatccaaga 1260 aagggtcact gatagagcgc aagaggagct ctggtcgggt taggaggaaa ggcgatgagc 1320 cccaggcctc gggataccac agtgaaggag aaacactgaa agagaagcag gctcctagaa 1380 atgcctccaa accatccagc agcaccaaca ggctgagaga ttttaaagag acagtcagca 1440 atatgatcca taacagacca tccctggctt ctcagaccaa tgtaggctct cactgcaggg 1500 gcagaggagg agaccagcct gacaaaaaac ctcctaggac cctgccttta cactctcgtg 1560 actgggaaat agagagtacc agcagtgagt caaaatccag ttcttccagc aagtatcgtc 1620 ccacatggag acccaaacga gaatctctga atattgacag tatctttagt aaggacaaaa 1680 ggaagcactg tggctatacc cagcttagcc ccttttctga ggattcagct aaagaattta 1740 taccagatga accaagcaag ccaccttctt acgacattaa atttggtgga ccaagccccc 1800 agtacaagcg ctggggccca gcacggccag gctctcacct tttagagcag cacccccgac 1860 taatccagcg aatggaatct ggctatgaaa gcagtgagag gaacagcagc agccctgtca 1920 gcctggatgc agccctgcct gagagctcaa atgtctacag ggatccaagt gctaagagat 1980 cagctgggtt ggttccttcc tggcgtcata tcccaaagtc gcacagcagt agcatcctgg 2040 aggtagactc cacagcatcc atgggtggct ggacaaagag tcagcctttc tctggtgagg 2100 agatatcttc taaaagtgaa ctggatgaat tgcaggaaga ggtggccagg agggcgcagg 2160 aacaggaact tcgaagaaaa cgggagaagg agttagaggc agcgaaaggg tttaaccctc 2220 atcctagccg cttcatggac ttggatgaac tgcagaatca ggggaggagt gacggctttg 2280 agaggtccct gcaagaggca gagtcagtgt ttgaagagtc actacatctg gaacagaaag 2340 gagactgtgc tgcagctttg gctctctgta atgaagctat ctctaaacta agacttgccc 2400 tgcatggtgc cagctgtagc acgcacagca gagccctagt cgataagaag ttgcaaatca 2460 gtattcgaaa agcacggagc ctgcaggatc gcatgcagca gcagcaatca ccacagcagc 2520 cgtcgcagcc ctcagcctgc ctcccaacac aggcggggac tctctctcag ccaacaagtg 2580 aacagcctat cccgctccaa gtattgttaa gccaagaggc ccaactggaa tccggcatgg 2640 atacagagtt tggggccagt tctttcttcc attcacctgc ttcctgccat gagtcacact 2700 catcactatc tccagagtca tctgccccac agcacagctc ccccagtaga tctgccttga 2760 agcttctgac ttcggttgaa gtagacaaca ttgaaccctc tgcattccac aggcaaggtt 2820 tacctaaagc accagggtgg actgagaaga attctcatca tagttgggag ccattggatg 2880 ccccagaggg taagctgcaa ggctctaggt gtgacaacag cagttgcagc aagctccctc 2940 cacaagaagg aagaggcatt gctcaagaac agctgttcca agaaaagaag gatcctgcta 3000 acccctcccc ggtgatgcct ggaatagcca cctctgagag gggtgatgaa cacagcctag 3060 gctgtagtcc ttcaaattca tcagctcagc ccagccttcc cctgtataga acctgccacc 3120 ccataatgcc tgttgcttct tcatttgtgc ttcactgtcc tgatcctgtg cagaaaacta 3180 accaatgcct ccaaggccaa agcctcaaaa cttcattgac tttaaaagtg gacagaggca 3240 gtgaggagac ctataggcca gagtttccca gcacaaaggg gcttgtccgt tctctggctg 3300 agcagttcca gaggatgcag ggtgtctcca tgagggatag tacaggtttc aaggatagaa 3360 gtttgtcagg tagtctaagg aagaactctt ccccttctga ttctaagcct cctttctcac 3420 agggtcaaga gaaaggccac tggccatggg caaagcaaca atcctctctg gagggtgggg 3480 atagaccact ttcctgggaa gagtccactg aacattcttc tcttgcctta aactctgggc 3540 tgcctaatgg tgaaacttct agcggaggac agcccaggtt ggcagagcca gacatatacc 3600 aagagaagct gtcccaagtg agagatgtta ggtctaagga tctgggcagc agtactgact 3660 tggggacttc cttgcctttg gattcctggg tgaatatcac aaggttctgt gattctcagc 3720 ttaagcatgg ggcacctagg ccaggaatga agtcctcccc tcatgattcc catacgtgtg 3780 taacctatcc agagagaaat cacatccttt tgcatccaca ttggaaccaa gacacagagc 3840 aggagacctc agaattggag tctctgtatc aggccagtct tcaggcttct caagctggct 3900 gttctggatg ggggcagcag gataccgcct ggcacccact tagccaaaca ggctctgcag 3960 atggcatggg gaggaggttg cactcagccc atgatcctgg tctctcaaag acttcaacag 4020 cagaaatgga gcatggtctc catgaagcca gaacagtgcg tacttctcag gctacacctt 4080 gccgaggcct cagcagggag tgtggggagg atgagcagta cagtgcagag aatttacgtc 4140 gcatctcacg cagtctcagt ggcaccgttg tctcagagag ggaggaagct ccggtttctt 4200 cccacagttt tgattcatca aacgtgagga agcctttgga aaccgggcac cgttgttcca 4260 gctcctcttc cctccctgtc atccatgacc cttctgtgtt tctcctcggt ccccaactct 4320 accttcccca accacagttc ctgtccccag atgtcctgat gcccaccatg gcaggggagc 4380 ccaatagact cccaggaact tcaaggagtg tccagcagtt tctggctatg tgtgacaggg 4440 gtgaaacttc ccaaggggcc aagtacacag gaaggacttt gaactaccag agcctccccc 4500 atcgctccag aacagacaac tcctgggcac cctggtcaga gaccaaccag catattggga 4560 ccagattcct gactactcca gggtgcaatc ctcaactaac ctacactgcc acactaccag 4620 aaagaagcaa gggccttcag gttcctcaca ctcagtcctg gagtgatctt ttccattcac 4680 cctcccaccc tcccattgtt catcctgtgt acccaccatc tagcagtctt catgtacccc 4740 tgaggtcagc ttggaattca gatcctgttc cagggtcccg aacccctggt cctcgaagag 4800 tagatatgcc cccagatgat gactggaggc aaagcagtta tgcctcccac tctggacaca 4860 ggagaacagt gggagagggg tttctgtttg ttctatcaga tgctcccaga agagagcaga 4920 tcagggctag agtcctgcag cacagtcaat ggtaaaggtt attcctttcc tttcctggag 4980 ctacaccttt ctttgtaaaa ctgtactgtg ggccgggcgc ggtggctcac acctgtaatc 5040 ccagcacttt gggaggctga ggcgggtgga tcacgaggtc aggagattga gaccatcctg 5100 gccaacatgg tgaaaccccg tctctaccaa aatacaaaaa attagccagg cgtgacggtg 5160 cgtgcctgta gtcccaacta ctcggaaggc tgaggcagga gaattgcttg aacccgggag 5220 gcagaggttg cagtgagccg agatcgcacc actgcactcc agcttggcaa tagagtgaga 5280 ctccatctca aaaaacaaaa caaaacaaca acaaaataaa ctactgtggc agcgttggta 5340 ccctgcatca ctgccatggt tgtgctattc tcatctcaac atagaattgg tgggttctcc 5400 taagggtgtc aggaacctct aaaaagatgt gattctttgg gaggggatat ttgaaattcc 5460 aacttccatt ccccctagca aaaggaagca gctgctgttt aagggtttta tctgagccac 5520 tttaaagatg aatccatggt attactctgg atactagcca ttccttagga ttttaaggtc 5580 acattttatt cctggatgct ttatgtcccc acctccacct gagccctcat cctctgttcc 5640 ctactatact cccaacttct actctttgtt ttatccacct atccctatta cctgaccctt 5700 tgtcttccct gtctcccatc cttgggggga catgtagccc tgtggtcatg gttctgatga 5760 catcatcagg gcagcccccc tgcccaggta ttatggcctg tcagcattcc ctgtgccctc 5820 caaaccttag gcctagaatg cggagctgcc aacataacat tcaccctttt gaacagatgg 5880 agtcaggcac actaacacag ccttctgtcc tcaataacac agccattatt gccacttgct 5940 cagtcgtcaa tgtaaaccct cagagtcagc tgaactattt taggccaaac atactgtttt 6000 tgtaaagtat ttttcattaa taaatctata agacagttct atttaaaaaa aaaaaaaaaa 6060 aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaacaaaaaa aaaaaaaaaa aaaaaaaaaa 6120 aaacaggtgg gggccgcgcg cgggcgcgcc cccgagagaa aatttccaca aacacccgtg 6180 ggggggcggc gggcgcccca agtgagtgac agagaaagaa agacgaggag cacaacagga 6240 ggtccgtcct ccagaagaaa acaaccgcgt gcggcacaga acaaaggagg tggcgggggg 6300 tgcgctccac cacgacaaat aagaaaaccc cgcggggggg ggaaaaacag cagacgagtg 6360 tcgtgaagaa caacaaccca caggagagag gcctcgtgga caaggcacac agggggtgct 6420 cacaaaacaa gggggtacaa agaaggagac gcaagaaaac ataattgccc 6470 119 435 DNA Homo sapien 119 gtataatcat ataggcgcat ggttctctaa tgctgctcga gcggcgcgtg tgatggatgc 60 gtggcgcggc gaggtacctc tcaacactga gaactgtagt agttgaaacc actgttctag 120 tgggcagtta gaacagttgt tttccccgtc ttgttcccca cagagctgcc caagttatta 180 tctgctcctg gggttggacc atctgtttta tgacagttat gatattgttg tttaaaaaaa 240 atccaaattg ttactttgat ttatatgatc taactctgaa tcacggaagt attactatga 300 tgttcaaaac tctgattgac tctacttgct ttaaaaactc tcagatccct tctgcattta 360 tcatcagaga tcggtaaaga tgacaacaag caggtctaaa gttctgagat gttagcacat 420 acccttttca caatt 435 120 1262 DNA Homo sapien 120 ggccgagttt tttttttttt tttttttttt tgtttttttt tttttttttt tttttttttt 60 tgttttagat atgttgcttt tattcaaaag aataaaatgc ttgacaaact ctttaatcac 120 aaggtttgaa ccaaaccacc agtcttctac aacaactctg tgaggtaggt atctgcatag 180 ccacaaggga tccacatagt cctttcttcc cttgtacctc tcaaacactg agaattgtag 240 tagttgaaac cactgttcta gtgggcagtt agaacagttg ttttccccgt cttgttcccc 300 acagagctgc ccaagttatt atctgctcct ggggttggac catctgtttt atgacagtta 360 tgatattgtt gtttaaaaaa aatccaaatt gttactttga tttatatgat ctaactctga 420 atcacggaag tattactatg atgttcaaaa ctctgattga ctctacttgc tttaaaaact 480 ctcagatccc ttctgcattt atcatcagag atcggtaaag atgacaacaa gcaggtctaa 540 agttctgaga tgttagcaca tacccttttc acaatttagg aagctttaag atcatttagt 600 atttttttat gttacaaaat ttggtacaat acacctcttt caggaaagtc ttagtagtaa 660 ctccaaatat tataattatt gtaaccagaa ttgtgacact tggagcagaa tgcatgcaca 720 caaaataaaa tcctgtcaaa aaatgacatc accattcccc cacaccaaat gtgtaattgg 780 taggaaatgc atttccagtc tggtacatgg cagtgtgaca aactcctact cactcgcttt 840 tcaagttggt gactgcagct gaaatgtttt tctgtgatgt atgccaccct tttacctatt 900 tgatttggaa gtgtagaatt cggattcatg tcatctccac agacctttcc tcttaggagt 960 gcctaagctg tcttactctg atggaggtat aatgtagcac gaaagacttc caaagaacca 1020 gtttctctct tgctgttcct cttaacaact ttcacgtcta tctaaacatt ctatgcagga 1080 gtcctactaa gaaattttgg tgtaatgcca ctttgatcag ttatttgttg tatgacttca 1140 ttcaaaaaca ctttcatcaa tagcatgggg attgtatcta tgaaagggaa gttggtgtcc 1200 tgcgttcctc acaaaattat ccaaaggata aaatgaaaag tatgtgagaa acctgcttta 1260 at 1262 121 562 DNA Homo sapien 121 ggtaccaact tgagtgcctc ctaaaagtgt aaccttgggg gcggggatac agaaggatga 60 tgctgacaat ggaatttaaa aacaaacagc aacattttgt ggtgtctaca ggcgtggggg 120 tggaggagct gcagcgtcac catgggaaca aaagtctccc acgcatctca ggcccgagga 180 atctttaaag agggagagtg ggcatgggag gaggacttaa gctattagtc atattttatt 240 tcgaaaacta gatcttaagt aactgtagca aaatgttaac aattcttacc ttggaatacc 300 ggttacatgg gattcatgtt actctatttt ttcatcatgt gcaaatattt tcatattttg 360 acaattaaaa ctaaatagta gctttttata aaagtggcat atgcactgaa gtataatgtg 420 ctaatttggg attcgtttaa ataaaacagc tttcttacaa aaaaaaaaaa aaaaaaaaaa 480 aaaaggttgg gggaaacaag ggcaaaaggg gttcccgggg ggaaatggtt accgggtcga 540 aatttcacaa ttggagaaaa ac 562 122 695 DNA Homo sapien misc_feature (13)..(13) a, c, g or t 122 ctggagcatg gtntgcagga gtgcaagact gcaagcctcc tccacggcca ccactccagg 60 cctggataaa gaattcgtgg catatttcag ggaacagaat gtcccctggg gcgaaagggg 120 atgaagtcat tctacttgta ccaacttgag tgcctcctaa aagtgtaacc ttgggggcgg 180 ggatacagaa ggatgatgct gacaatggaa tttaaaaaca aacagcaaca ttttgtggtg 240 tctacaggcg tgggggtgga ggagctgcag cgtcaccatg ggaacaaaag tctcccacgc 300 atctcaggcc cgaggaatct ttaaagaggg agagtgggca tgggaggagg acttaagcta 360 ttagtcatat tttatttcga aaactagatc ttaagtaact gtagcaaaat gttaacaatt 420 cttaccttgg aataccggtt acatgggatt atgttactct attttttcat catgtgaaat 480 attttatatt ttgacaatta aaactaaata gtagcttttt ataaaagtgg catatgcact 540 gaagtataat gtgctaattt gggattcgtt taaataaaac agctttctta gaataaaaaa 600 aaaaaaaaaa aaaaaaaggt tgggggaaac aagggcaaaa ggggttcccg gggggaaatg 660 gttaccgggt cgaaatttca caattggaga aaaac 695 123 386 DNA Homo sapien 123 aacccctggc caggcccagc tgccacaccc tttctgggag aagcatggcc tacagaatga 60 agagggggac caggaacccc tgtgggagag gcttagacct gaagcagtgc ccactctggc 120 tcctcctgcc ttggctgact gggttcctgg accatgtgca tttcactggg ccatgggatc 180 tacatctcct tgcatcccca gctggtctga tccctgccag ggccccttcc ttcctgctca 240 tggtcttcag gtggcctgat catggaaagt aaggagttag gcattacctt ctgggagtga 300 accctgactc catcccccta ttgccaccct aaccaatcat gcaaacttct ccctccctgg 360 ggtaattcaa cagttaaaag aagctt 386 124 654 DNA Homo sapien 124 atgataaacc acctcagccc ccaccaagcc gccgcacccg tagaccagac cccaaggacc 60 ctggccacca tgggccagag agcattacct tcatctctgg ctctgctgag ccggcccttg 120 agtcccccac ctgctgcctg ctctggcgac cctgggtgtg ggagtggtgc cgggctgcct 180 tctgcttccg ccgctgccgg gattgcctcc agcgctgtgg aggccgtgtg cggggatgca 240 gcccctgcct gtctactgag gactcccctg aggggactgc tgaagccaac tggtccaagg 300 agcacaatgg agtgcccccc agccctgatc gtgcagcccc ccgccggcgg gatggccagg 360 cgggctgcaa gtcaaccatg ggcagcagct tcagctaccc cgatgttaag ctcaaaggca 420 tccctgtgta tccctaccga gaggccacct ccccagcccc tgatgcggac tcctgctgca 480 aggagccact ggccgatccc ccacccagcg agcacagcct gcccagcacc tttgccagta 540 gtcctcgtgg ctccgaggag tactattctt tccatgagtc ggacctggac ctgccggaga 600 tgggcagtgg ctccatgtcg agccgagaaa ttgatgtgct catcttcaag aagc 654 125 684 DNA Homo sapien 125 acatgcagat gtgcatgtta cagagataaa gtgatcgaga caaggactga ctgggtatag 60 aaggaagaca gactcctgtc ttcactccta aatgcagttc tttggaatca ccctactgtg 120 atgggcgtag tagggagcca tcagctagga agaaacgtgg gagatgtgaa ttccaagagt 180 tgcctggaca gggcaagtca tgttagcgtg ggtcacactt ccaagatatt taaagcaaat 240 acaaaacaga acagaggatt caaaccgcaa gtatgggaga tttaggccct gcagaggcag 300 accattcctt agtatctcac aaagcagagt aatactggag gcagagtagg gggtggttgg 360 agagcagtta gtaccaataa caatgaagtc tgtgtttgat ctgatcgata ctttccagtc 420 ccgaatcaaa gatatggaga agcagaagaa ggagggcatt gtttgcaaag aggacaaaaa 480 gcagtccctg tgagaacttc ctatccaggt tccggtggag gaggaggttg ctggtgatct 540 ctgtcctaac gatgaagact gggctattca caggcagctc tctgccctca gtggtcaggc 600 gtgcacattt ggtctgcgcc acataacatt ctgaagcttg ggtatcatgg tcatagtgtt 660 ccgtgtgaat gtatcgtcac atcc 684 126 2671 DNA Homo sapien 126 ctgccgaaga gttcaaaaca gaagagcaag atgcctcagg gagtatagaa tttggtgtat 60 cttttcctga tagggaatca tcatctatgg aaacatccat cgaaccaaaa gcaactgaaa 120 cttctcacac agagggaatt actgccattg aggagagctg ggagtctatg tttaacgatg 180 atggtgactg cctggatcca cgtcttctac aagagttatc agggaatacc aagagcagag 240 agagcatcca ggaacctaga tctgattact acaatcatga agttcctgat attgacctca 300 gtgattgtga attcccacat gtcattgaaa tttatgactt tccccaagaa tttcgtactg 360 aagaccttct acgggttttc tgcagttatc aaaagaaagg atttgatatt aaatgggtgg 420 atgatacaca tgccctagga gtattctcca gtccaattac agctcgtgat gcgttgggta 480 ttaaacacac catggtgaag attcgtccct tgtcacaggc cacaagagca gccaaggcca 540 aagctagagc ttatgctgag ttcctccagc cagcaaagga gcgtcctgag acttcagcag 600 ccctagccag aaggttagtc atcagtgccc ttggggttcg aagtaagcag agcaaaaccg 660 aacgagaagc agagctcaag aaactgcaag aagccagaga gagaaagcgg ttggaagcca 720 agcaacggga agacatctgg gaaggcagag accagtctac agtttgaaca tcactcaatg 780 aaagggataa ttccatgaat cagaaaatgt ttccatagcc ttcagataag atgatccttc 840 cagagctcta tgtacatgca gatgtgcatg ttaaagagat aaagtgatcg agacaaggac 900 tgactgggta tagaaggaag acagactcct gtcttcactc ctaaatgcag ttctttggaa 960 tcaccctact gtggtgggcg tagtagggag ccatcagcta ggaagaaacg tgggagatgt 1020 gaattccaag agttgcctgg acagggcaag tcatgttagc gtgggtcaca cttccaagat 1080 atttaaagca aatacaaaac agaacagagg attcaaaccg caagtatggg agatttaggc 1140 cctgcagagg cagaccattc cttagtatct cacaaagcag agtaatactg gaggcagagt 1200 agggggtggt tggagagcag ttagtaccaa taacaatgaa gtctgtgttt gatctgatcg 1260 atactttcca gtcccgaatc aaagatatgg agaagcagaa gaaggagggc attgtttgca 1320 aagaggacaa aaagcagtcc ctgtgagaac ttcctatcca ggttccggtg gaggaggagg 1380 ttgctggtga tctctgttcc taacgatgaa gactgggcct attcacagca gctctctgcc 1440 ctcagtggtc aggcgtgcaa ttttggtctg cgccacataa ccattctgaa gcttttaggc 1500 gttggagagg aagttggggg agtgttagaa ctgttcccaa ttaatgggag ctctgttgtt 1560 gagcgagaag aaaaaaaaga tgaagaatga gaacgcagac aagttactta agagtgaaaa 1620 gcaaatgaag aagtctgaga aaaagagcaa gcaagagaaa gagaagagca agaagaaaaa 1680 aggaggtaaa acagaacagg atggctatca gaaacccacc aacaaacact tcacgcagag 1740 tcccaagaag tcagtggccg acctgctggg gtcctttgaa ggcaaacgaa gactccttct 1800 gatcactgct cccaaggctg agaacaatat gtatgtgcaa caacgtgatg aatatctgga 1860 aagtttctgc aagatggcta ccaggaaaat ctctgtgatc accatcttcg gccctgtcaa 1920 caacagcacc atgaaaatcg accactttca gctagataat gagaagccca tgcgagtggt 1980 ggatgatgaa gacttggtag accagcgtct catcagcgag ctgaggaaag agtacggaat 2040 gacctacaat gacttcttca tggtgctaac agatgtggat ctgagagtca agcaatacta 2100 tgaggtacca ataacaatga agtctgtgtt tgatctgatc gatactttcc agtcccgaat 2160 caaagatatg gagaagcaga agaaggaggg cattgtttgc aaagaggaca aaaagcagtc 2220 cctggagaac ttcctatcca ggttccggtg gaggaggagg ttgctggtga tctctgctcc 2280 taacgatgaa gactgggcct attcacagca gctctctgcc ctcagtggtc aggcgtgcac 2340 attggtctgg gcgccttacc ttctgaagct taagcgtgcg cacggactgg gggcccgttc 2400 aactggcccc attaagggac cccgagataa cgagaaacgt acaccccatg gtgaaaaaca 2460 ccgcacaaat ccacggaccc ggagacaacc caggccaggc gcaaaaagca agaccacacg 2520 gatatcaccc aaggcagcga gaagggacca cacacacacc cgcacaacag gacacccaag 2580 cggcgccaca acagtcacga caccacaagg ccacgaagca acacacagaa acatacacag 2640 cagcacacgg ccatacaacc gcccacacag c 2671 127 420 DNA Homo sapien 127 acgggccgca gtgttgatgg atgcggcgag gtaactctct ctcccttaag agttatgagt 60 tatcaagagg agacttctta aagacagcaa cgcaattctt gtaacttgtg taaatagccc 120 catctttcag agtgatacca tttctacatt tgataatgcc tgtattcctg taggatgtat 180 atagtttagg ggattttttt ttggttgggg ttttggtttt ttagaaggtc aatatgtctg 240 gttttattta tgtgcttgaa aaagatcatt tgaaaaaaat aaatacattt tcaaccacaa 300 aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa ggcgcggggg ggaacccggg gcccagagcg 360 ggccccgggg ggcgaattgg gttctcccgg cccacattcc cccaaaatat tggcacacag 420 128 2269 DNA Homo sapien 128 taccgaggag ggaacaagct acatgctatt ttgtttgtag tattgtggaa cagtcttgtt 60 atggagtgcc agcttagagg ttgttgcaaa cttgtctaga agtgagagca tggttttttt 120 tagccctttg agagtctaca tctaatgaac attcttgctc acccataaat aacgtcaagc 180 ctcaatgtca ccgtcacgtt gggatactct ttctcatctg gcatcctaga caggacaagg 240 ttggttacct ttccttccat gaaccatgaa cctgtgacgg catcattcat cctgacttca 300 ccaagctccg cctgtgggtg aggccagagc tcccactggc aatttttaga agagccagag 360 gctccctgct tcctctagaa ataacagttc agggtgaagc atggagggtt tcagttccca 420 gacaatggaa ccatttagag acaacacagt tggacatttc cactttttcc ttgattcctg 480 gaagtccagt gggttctgca gctgaaaaag ccctgggtcc cagcagcaga gagacaggac 540 agaggggatg cttgggcggg gagggacggt aacctgcaga acagattcca tttttataga 600 acgagtacac gtttgctaaa acagtcctgc tttcccagac tggattccca ccacagggac 660 agtcggaact caggactagc tccagcgaca tctttcctcc gaattcaagc cttctatcac 720 aatgtcaaaa cagctattta taaagccatt ttcattgtac ttgataacag cacgagtccc 780 aaaactttta gaaataaaat aggacattgg cttgattgaa aagagggact ttttaaaaat 840 tgttctttcg tcagaagcct tttggatgac ttacaatagc tctgatgaag ataccacccc 900 agcgtcagtc caataggtca gtgagtttca acaggcatcc atccctccca tgaagggatt 960 ctggtgatgg gaagtttctg taatgacagg aaagcattga ccctcattga ttgtcaactt 1020 tggtattagc catgaaagac aggatgctca ttgggtgttc tgtagagtga ggaatgctgc 1080 ctattccctc ccagaacgtc tgacccaggg gtgtgtgttg aggagccctg ggggaaatgg 1140 accaagtttt cccacagagc agtattaggc tgaagagcag gtgactggta ggccccagct 1200 cccatcattc cctcccaaag ccattttgtt cagttgctca tccacgctgg attccagaga 1260 gttttccaat ttgggaagcc atgagaaagg tttttaaatc ttgggaagat ggagagaggg 1320 acataggata gttgactcca acatgacagg aagaggctgg agattgggaa ttggccatca 1380 accaagcctg tagtagtaaa gccatggtcc cgcattggaa ttacttgggg aacttataca 1440 gttctgatac ccaggctctc ctagaccagt tcaaccaatt ctaggtgggg gactcaggca 1500 tcagtgtgtt tcgtagctcc ccgggtgttt tccctgtgca gccgagcttg ggaaactgcc 1560 atgctttttg gatgtcaagg cgctgttgga ggctgggtgt gacagcacag agccaggttg 1620 tcttgtggaa accacagcca cgggtttgcc actggctcag catggcctca ctgccagtcc 1680 cagcctggct gagggacaag atggtttctc ttgggagttc ctgagtggag cacccttcca 1740 ggctttttga aagccagctg atctgtggag ccttgttaag ggactcaata cggtgtttgg 1800 atattgatgt ttttccttga gactgtcttg tccatcaata aagatggagg atgtctcctc 1860 tttgaacccc gcttccccac cagtactctc tctcccttag agtttatgag ttattcaagg 1920 aggagacttc ttaaagacag caacgcaatt cttgtaactt gtgtaaatag ccccatcttt 1980 cagagtgata ccatttctac atttgataat gcctgtattc ctgtaggatg tatatagttt 2040 aggggatttt ttttttgttt ggttttgttt tttagaagtc aatatgtctg gttttattta 2100 ttgcttgaaa aagatcattt gaaaaaaata aatacatttt caaccaaaaa aaaaaaaaaa 2160 aaaaaaaaaa aaaaaaaaag gcgcgggggg gaacccgggg cccagagcgg gccccggggg 2220 gcgaattggg ttctcccggc ccacattccc ccaaaatatt ggcacacag 2269 129 750 DNA Homo sapien 129 gccgcccggg caggtaccca agtttcagtt acacaggagg catgagattg atctagtgca 60 aaaaatgatg agtataataa ataataatgc actgtatatt ttgaaattgc taaaagtaga 120 tttaaaattg atttacatac atattttaca tatttataaa gcacatgcaa tatgttgtta 180 catgtataga atgtgcaacg atcgagtcag ggtatctgtg gtatccacca ctttgagcat 240 ttatcgattc tatatgtcag gaacatttca agttatctgt tctagcaagg aaatataaaa 300 tacatttata tgttgactat ggcctatcta catgttgcaa ctaaacacta gattttactt 360 cctttccaac tgtgggtttg tattcattta ccaccctctt ttcattccct ttctcaccca 420 cacactatgc cgggcctcag gcatatacta ttctactgtc tgtctctgta agcgattatc 480 agttttagct tccacatatg agagaatgca tgcaaagttc tgtctttcca tgcctggtct 540 tatttcactt aagcaaaatg acctccgcgt tccatccatg ttatttatat tacccaacta 600 gtgttcataa aactagtata tacaccacat agtataccac agaaacggac cactgcggat 660 aaacaggatt tctggtccac acttttgtcc catacgggac cgtggggcaa tctgattacg 720 cgcacagcaa gagcaaccca gtaagaaaca 750 130 738 DNA Homo sapien 130 gcgtggtcgc ggccgaggta ctgtgaatta cggatgctct ttgaaggaaa gaaatatcga 60 ttctaatgtt cttcagaagt tctggcaggg ataagcagga catcgactgg aacgtatgct 120 aaatgaaagc agacaaattt ctattttctt acctgagcaa atattttatt gaaactgctt 180 atgtatgcca aaggagccca caacttcagc tacacaactt tttgtattga aagaactcat 240 actttttgta gcttttattt cacatttaat ttaaagtgac ttttagcact aaaatgccta 300 gaagatttta ctccagacct ataaggaaat gtttagtttt tatgaaaaat gacaagtcga 360 tggttaaact tctcatgtct ttggtgcttt ggccctaata gcactggaca acaccacgac 420 cacatggaaa catatttttg gaagcaaaac tttaatttta tataacgtat gctatggaga 480 gctaagacaa tttaaggact acttgttttc tatttttttt cttaataaaa tggaatccac 540 tgtgttgaag actcttgata ttcatgtgct tgtctaacca ttttttgttt tataattaga 600 ataaaatata gttgtgataa tggtcatcga atggattttg tttggaaagc tacatcttat 660 ttgtgaaatg ttttttaaaa tcagagtaac tatcaactga ttcagctttt tgttgttttg 720 ttcttggtat aatacttg 738 131 1875 DNA Homo sapien 131 tggcaacgat ctggaccgct acaacccgct aagctccagc gccttgtgcg caacgcgctg 60 gcgcacgtgg tgccaaggag cgcgagctga gctggcgcac tcggagagtt tcgccgcctg 120 tgccgctacg gcaagcgcga gttcaagatc ggcggcgagc tgcgcatcgg caagcagccc 180 taccggctgc agattcagct gtcggcgcag cgcagccaca cgctcgagtt ccagagtcta 240 gaggacctga tcatgggaga agcgacgcaa cgacccagat cgggcgcgcg gcccgtgctg 300 caggagctcg ccacgcacct gcacccggcg gagccggagg agggcgacag caacgtggcg 360 cggactacgc cgcctcccgg gcgcccccct gcgcccagct ccgaggagga ggacggagag 420 gcagtggcac actgatgggc gagctgagcg cagagctgcg aaggggaact gtttgcagta 480 gcagccgctg ctccctttct ccctctcttc ctccctcttt tgccactgtc tgggccccat 540 ctgggattcc tgggcccttt ggaaaagagt tggtgaaatg cgcagccggc tgtggacggg 600 ggaggaggaa ggggacagag ggagcaggaa taagactgta gaactgtttt gtactgtgaa 660 ttacggatgc tctttgaagg aaagaaatat cgattctaat gttcttcaga agttctggca 720 gggataagca ggacatcgac tggaacgtat gctaaatgaa agcagacaaa tttctatttt 780 cttacctgag caaatatttt gttgaaactg cttatgtatg tcaaaggagc ccacaacttc 840 agctacacaa ctttttgtat tgaaagaact catacttttt gtagctttta tttcacattt 900 aatttaaagt gacttttagc actaaaatgc ctagaagatt ttactccaga cctataagga 960 aatgtttagt ttttatgaaa aatgacaagt cgatggttaa acttctcatg tctttggtgc 1020 tttggcccta atagcactgg acaacaccac gaccacatgg aaacatattt ttggaagcaa 1080 aactttaatt ttatataacg tatgctatgg agagctaaga caatttaagg actacttgtt 1140 ttctattttt tttcttaata aaatggaatc cactgtgttg aagactcttg atatcatgtg 1200 cttgtctaac cattttttgt tttataaatt agaataaaat atagttgtga taatggtcat 1260 cgaatggatt tgtttggaaa gctacatctt atttgtgaaa tgttttttaa atcagagtaa 1320 ctatcaactg attcagcttt ttgttgtttt gttcttggct ataatacttg tgactcatga 1380 agaattatgt tgacaaacag gataaattcc acatgcattt tatttcccag tgagttgtat 1440 aaactttatt tttgttgaag gttgtatgtt aaatcaatgt tacattctta tatcacttct 1500 tgagaaggaa gttccgattt gaaattgtat catttccttc aaaatgaagg gcagtgctta 1560 gttaaataaa agattgatga tatcttttaa gccaaaaaaa aaaaaaaaaa aaaaaaaaaa 1620 aaaaaaacga accaaaccaa taaaaacaag aagcacacag accgaacacc acacacacaa 1680 gccaccagag ctcacataac gcgcgggcaa acatccacac ggccacacac agcaacccac 1740 tatgagagcc accccgcgga acaaaagacc ccacacacaa ccagagacaa gaaacctgcg 1800 agccacgccg tccacaccca caaccacgaa tagtcacctc agtaacaaaa caaacacaga 1860 cggaggcgcc gacaa 1875 132 828 DNA Homo sapien 132 tggtcgcggc cgaggtacaa taggtctctt gaatttattc ctcctgtcta attgaaattt 60 gtatcccttg accaacatct tcccagtcac acccccatcc ctctggtaac catcattcta 120 ctctagttgt atgagttcaa tttttttaga ttccatttat aagtgattta attaatatct 180 ttatcctctt tccagataat tcaaggacct tagcatttta actctagtca actgtaatat 240 tacattccat cgtattgcag tattttagtc ttcttctatt aagccttcca aattggatat 300 tagcattatt gtggttgttt cacattagca ttattgtggt tgtttcagat agtcaatatt 360 gatgcagatt tacctgaata ttacccatga ttaccatcat tccttctttc tacttagatt 420 tccatcatcc ttcttcttga aatataattt ttaaaaggtc cattgaagaa gttctgttga 480 tggtaaatac agttttactt tctttgaaaa tatctttatt ttgcccacat cagttatttt 540 attgttcagt attaagaaaa cctaattcct gtgttttctt cccatcattg ttgatattga 600 gttgtgtgcc atcaggcaaa tgtcattact ttttagatat tctaaacctg ttgtttcttt 660 aagtaagtac attgtctccc ccttaatctg ttctccttcg taatgtttta ttatttgtct 720 cactattatg gattctggac aggtttcttc tgggtccttc tttcaggttg ctattctcta 780 ttcaggtgtg tttatctgct atttatcatc cctccagttt tttccttg 828 133 1023 DNA Homo sapien 133 tggtcgcggc cgaggtacaa taggtctctt gaatttattc ctcctgtcta attgaaattt 60 gtatcccttg accaacatct tcccagtcac acccccatcc ctctggtaac catcattcta 120 ctctagttgt atgagttcaa tttttttaga ttccatttat aagtgattta attaatatct 180 ttatcctctt tccagataat tcaaggacct tagcatttta actctagtca actgtaatat 240 tacattccat cgtattgcag tattttagtc ttcttctatt aagccttcca aattggatat 300 tagcattatt gtggttgttt cacattagca ttattgtggt tgtttcagat agtcaatatt 360 gatgcagatt tacctgaata ttacccatgg attaccatgc attccttctt tctacttaga 420 tttccatcat ccttcttctt gaaatataat ttttaaaagg tccattgaag aagtgtctgt 480 tgatggtaaa tacagtttta ctttctgttg aaaatatctt tattttgccc acatcagtta 540 ttttattgtt cagtgattaa gaaaacctaa ttcctgtgtt ttcttcccat cattgttgat 600 attgagttgt gtgccatcag gcaaatgtca ttacttttta gatattctaa actgttgttt 660 gctttaagta agtacattgt gctcccctta atctgttctc ttcgtaatgt tttatttatt 720 tgtctcacta taatgaattc tggacaggtt tcttctggtc tttctttgca gtttgctaat 780 tctctattca gctgtatcta atctgctatt taattcatcc atcaagtatt ttttccttag 840 tattttgttt taataatttt atttactatt tctagatttt tttctaatca tcctggtctt 900 tgtcatagta tcttcttctt tatatacatt ttatttatgt atctgataac attaataact 960 taaacctttg taagttataa gtatgttttt agttttggtg ctgatttggt tcaaataaac 1020 ata 1023 134 757 DNA Homo sapien 134 gagcggcgcc cgggcaggta ccttcgtgcc cctcagtagt tgttttagcc taatgtagag 60 tcaatctagg acttataatt attcatcatg attttgagta gattgtaatc atcaagaatt 120 tttcatagat cgtttacttc caattgaatt tagctcagaa gtgattgctt tctctttatt 180 tgagatagga gctctcgcac tgtcgccagg ctaggagtgc aagcggtcat gatcgtcggc 240 tcactagcaa cctctgcctc ccgggttgaa gcagatatac ccctgacctc aagcctcctg 300 cagtagctag ggactacagg tagttcatcg cttgtcctta gcttggaaac taggatgcac 360 aaacacatgg gttattatac tcgtacacgg agctggtcac acaacggaac tagactctct 420 ctccaaatgt gataccacac agacaacact cagaactacc ttcgagcctt acttaagatc 480 atcccttcac tgatctaaca aacttacaaa cattaataca accagatact gcgtctcgac 540 tattgcacgg caaatcaaaa tacaacaggt tctccactaa agaccaggtg gtgacatgtc 600 ctagagatca acagaacaat ctaatcctga ccctcacgcc aactatgatg acacgatggc 660 cgctggccca cacaggaagg ccgacacggg ccgcgctcaa agaccaccca tgtccggacc 720 tagcctaaaa aaaactcacg ccccgccgcc cctacct 757 135 1513 DNA Homo sapien 135 gcgggagcct gggcggcgag ccgggtgtga gctgcctgaa aatgcactcg gatgccgccg 60 ctgtcaattt tcagctgaac tctcatctct caacactggc aaatattcat aagatctacc 120 acacccttaa taagctgaac ctaacagaag acattggcca agacgatcac caaacaggaa 180 gtctgcggtc ttgcagttct tcagactgct ttaataaagt gatgccacca aggaaaaaga 240 gaagacctgc ctctggagat gatttatctg ccaagaaaag tagacatgat agcatgtata 300 gaaaatatga ttcgactaga ataaagactg aagaagaagc cttttcaagt aaaaggtgct 360 tggaatggtt ctatgaatat gcaggaactg atgatgttgt aggccctgaa ggcatggaga 420 aattttgtga agacattggt gttgaaccag aaaacgtgag tcaaacttac tgagttgggt 480 gaatcagttg gttgtttttc atacttaaat ctttgttctt tagcaaataa atagaataat 540 taaaaagtag tggtatgtta gtttttatga agcagtctaa gaaataagtt ctaattctag 600 tttgacttat aagcagattc tccattcttg taagtgatat ggtgtaacta cagttatttt 660 ttctctcatt taatttcttg tatgtaaaag gtacagtaag ccagatgctt acaaaatggt 720 gtggccacat gtgcctacaa tgacggatca actggaggcc acattgtacg ctgtgtacct 780 tcgtgcccct cagtagttgt tttagcctaa tgtagagtca atctaggact tataattatt 840 catcatgatt ttgagtagat tgtaatcatc aagaattttt catagatcgt ttacttccaa 900 ttgaatttag ctcagaagtg attgcttttt tttttttgag ataggagctc tcgcactgtc 960 gccaggctag gagtgcaagc ggtcatgatc gtcggctcac tagcaacctc tgcctcccgg 1020 gttgaagcag atatacccct gacctcaagc ctcctgcagt agctagggac tacaggtagt 1080 tcatcgcttg tccttagctt ggaaactagg atgcacaaac acatgggtta ttatactcgt 1140 acacggagct ggtcacacaa cggaactaga ctctctctcc aaatgtgata ccacacagac 1200 aacactcaga actaccttcg agccttactt aagatcatcc cttcactgat ctaacaaact 1260 tacaaacatt aatacaacca gatactgcgt ctcgactatt gcacggcaaa tcaaaataca 1320 acaggttctc cactaaagac caggtggtga catgtcctag agatcaacag aacaatctaa 1380 tcctgaccct cacgccaact atgatgacac gatggccgct ggcccacaca ggaaggccga 1440 cacgggccgc gctcaaagac cacccatgtc cggacctagc ctaaaaaaaa ctcacgcccc 1500 gccgccccta cct 1513 136 738 DNA Homo sapien 136 gcgtggtcgc ggcgaggtac caaccccagc acaccccaac agcctttcct cggccccctc 60 ctcaggcctc ctaattactc tttctcagcc tggagtgtgg ggccgttacc gtcctcttcc 120 cccttctcct tccatactgc acttaacctt gctggaagat ttaatgatgg agatttaggg 180 caactgtggc tgcttgggac ccttccctgg gaccaaagga acttaaaacc caatacctga 240 cactggaatg aaatccaagt ttttaaatat cacctttcaa tcactcacag atctcacatc 300 tatcttaaaa tactcagcct cactccttaa ctgagtgctt gcctgagagg gagaaaagtt 360 ccattttaaa aacgtattca ctttactgat tactgtgcaa tttgaattaa gtcacgattc 420 tttagtcatg gaggtcgaga atctcagatt caaattgtca gagaccatga tttagaagtc 480 taccaaacac ccagtttcct tccactgttt tagggtaaca ggaaaacatg agattggggt 540 ggtgtccgct attaaatgga accacacatc atgaaattca attctcatgt taagacattc 600 tgtattgtgg gatgtcaaaa gtatctccca aaactttcgt ttgacctgtc agagtgggga 660 tggttactcc ctatacttca gtttgtttca caagcttggc gtaaccaggc atagtgttcc 720 gtgtgaatgt tcgtccac 738 137 1350 DNA Homo sapien 137 atggttatgg agaagcccag tccgctgctt gtagggcggg agtttgtgag gcaatattat 60 actttgctga ataaagctcc ggaatattta cacaggtttt atggcaggaa ttcttcctat 120 gttcatggtg gagtagatgc tagtggaaag ccccaggaag ctgtttatgg ccaaaatgat 180 atacaccaca aagtattatc tctgaacttc agtgaatgtc atactaaaat tcgtcatgtg 240 gatgctcatg caaccttgag tgatggagta gttgtccagg tcatgggttt gctgtctaac 300 agtggacaac cagaaagaaa gtttatgcaa acctttgttc tggctcctga aggatctgtt 360 ccaaataaat tttatgttca caatgatatg tttcgttatg aagatgaagt gtttggtgat 420 tctgagcctg aacttgatga agaatcagaa gatgaagtag aagaggaaca agaagaaaga 480 caaccatctc ctgaacctgt gcaagaaaat gctaacagtg gttactatga agctcaccct 540 gtgactaatg gcatagagga gcctttggaa gaatcctctc atgaacctga acctgagcca 600 gaatctgaaa caaagactga agagctgaaa ccacaagtgg aggagaagaa cttagaagaa 660 ctagaggaga aatctactac tcctcctccg gcagaacctg tttctctgcc acaagaacca 720 ccaaagccaa gagtcgaagc taaaccagaa gttcaatctc agccacctcg tgtgcgtgaa 780 caacgaccta gagaacgacc tggttttcct cctagaggac caagaccagg cagaggagat 840 atggaacaga atgactctga caaccgtaga ataattcgct atccagatag tcatcaactt 900 tttgttggta acttgccaca tgatattgat gaaaatgagc taaaggaatt cttcatgagt 960 tttggaaacg ttgtggaact tcgcatcaat accaagggtg ttgggggaaa gcttccaaat 1020 tttggttttg tggtttttga tgactctgaa ccagttcaga gaatcttaat tgcaaaaccg 1080 attatgtttc gaggggaagt acgtttaaat gtggaagaga aaaaaacaag agctgcaaga 1140 gagcgagaaa ccagaggtgg tggtgatgat cgcagggata ttaggcgcaa tgatcgaggt 1200 cccggtggtc cacgtggaat tgtgggtggt ggaatgatgc gtgatcgtga tggaagagga 1260 cctcctccaa ggggtggcat ggcacagaaa cttggctctg gaagaggaac cgggcaaatg 1320 gagggccgct tcacaggaca gcgtcgctga 1350 138 569 DNA Homo sapien misc_feature (509)..(509) a, c, g or t 138 cgcccgggca ggtcgcccat gtgctgtgat gtcagtgagc gggcggagtt caggctggtc 60 agtgccaggt gctccttctc ccacccgaga acagtggcca ggttgctcct caggcaccct 120 gggcaactgc cccttccctt ccagtggggc ctgacctggc taccgagctt ggcagctaat 180 aggcgggccc ctcagcattc acgctcctga gctgctttat caaactagga ttgttccccc 240 aggtctaaga aaaccatcca ttcactgcaa agttagttat tactgcggat gggctaggag 300 ttagaggaag agagtgactc aaatcacaac acctcctgga cgaagctgga agcggattaa 360 aataccgggc ctaatttcag aacaacaaaa aaaaaagaaa aaaaaaaaaa agcgcgggcc 420 ggaacccagg ggccaaaagg gtgggtcccg gggggggaaa tctggttacc gcggcccaaa 480 attccccaaa aaatttgggg gggccaaang caccgcgctc tctgcccccc ccacgcccgc 540 cccccccccc acaacccatc gccgccccg 569 139 739 DNA Homo sapien 139 tatatcacta taggggactg ggtcctctag atgctgctcg agcggccgca gtgtgatgga 60 tccgggcagg tactgcctgg ttttacaaga attaatgcag tttcacagtg aagcatgtaa 120 gatattgaat tttagagaca atagaccaga tacctttcta atctcatttt attcattaat 180 gtcaaataat accattttta aaaatatggt gcttatttgt ctagcaagta acctatagaa 240 aagtattatt ttatacaaaa agatgattag gtcacataaa ggaattggaa tcttaagttt 300 aaaatacact tctgttttta gccagaaggg agaaacgatg gttggattta tgccattttt 360 caattaaaaa ccatgtggta ctacttgaag cagtttctga gtaaatggag gtgtttaaag 420 atttgtatta ttctctccca atgactagat agtagtattt tacaatggag acttaaaagt 480 tttttgtgtt ttattctttc gcttttctat gccctcaatc caaagaacac cagaaataca 540 cttgtagtcg gaaaacttgg gtttatcact cgcatcaagg aatgacacac accatgggcc 600 actctggagc ctctcaataa aaggatgttt caaaggaaca acaacaaaaa aaaaaaaaaa 660 aaaacgttgg gggaaacaca gggcacaaag tgtcccgggg gaaattgttt tccgccacaa 720 tccaaaattc acaaaaacc 739 140 1131 DNA Homo sapien 140 aagttgatag tatatccacc acctccagct aagggaggca tctctgttac caatgaggac 60 ctgcactgtc taaatgaagg agaattttta aatgatgtta ttatagactt ttatttgaaa 120 tacttggtgc ttgaaaaact gaagaaggaa gacgctgacc gaattcatat attcagttct 180 tttttctata aacgccttaa tcagagagag aggagaaatc atgaaacaac taatctgtca 240 atacagcaaa aacggcatgg gagagtaaaa acatggaccc ggcacgtaga tatttttgag 300 aaggatttta tttttgtacc ccttaatgaa gcgtgagtaa gaatttcctt taaaggaaaa 360 tctttaaatc atgtaaatga tgacaatttt taaataatga gtatgaggtg aagaattcat 420 tttaaaacat ctttctgaaa tctcttgtgt atattcatat ttgtactgcc tgttttacaa 480 gaattaatgc agtttcacag tgaagcatgt aagatattga attttagaga caatagacca 540 gatacctttc taatctcatt ttattcatta atgtcaaata ataccatttt taaaaatatg 600 gtgcttattt gtctagcaag taacctatag aaaagtatta ttttatacaa aaagatgatt 660 aggtcacata aaggaattgg aatcttaagt ttaaaataca cttctgtttt tagccagaag 720 ggagaaacga tggttggatt tatgccattt ttcaattaaa aaccatgtgg tactacttga 780 agcagtttct gagtaaatgg aggtgtttaa agatttgtat tattctctcc caatgactag 840 atagtagtat tttacaatgg agacttaaaa gttttttgtg ttttattctt tcgcttttct 900 atgccctcaa tccaaagaac accagaaata cacttgtagt cggaaaactt gggtttatca 960 cttgcatcaa ggaatgacac acaccatggg ccactctgga gcctctcaat aaaaggatgt 1020 ttcaaaggaa caacaacaaa aaaaaaaaaa aaaaaacgtt gggggaaaca cagggcacaa 1080 agtgtcccgg gggaaattgt tttccgccac aatccaaaat tcacaaaaac c 1131 141 887 DNA Homo sapien 141 gcgtggccgc ggccgaggta cactgaatta ttcacagtaa tcgcttggtt ggggaaaggg 60 ttagtaaatg ccaaaggaaa tacccacaga aatctcctac acagcttaga tgttgtgctg 120 gcatttaagg cccatgagtg atggtccatt ctgcagcttt tcatgccatg cctttccttt 180 gtgtgggggt ccacagatca gagtctgtct gtggcatcga cttccttatg tcctcattgt 240 tcccacccat tgctgggatg tccacgttgg acttctcaaa agtggcccaa gaatctaagt 300 gcaaaatctg tttggatttt tacaattttt tcctaatctt ttacagtctt ggtcattcct 360 atttcaactg caattttttt caatgacttg cctggtgtga atattttttt aaagcatcca 420 gtattaaaca aaaaaattta aacagctaaa aaaaaaaaac aaaaaacaaa cggctgggcg 480 aaaccagggc tcaataccgg ctccccgtgg tgctgaacac tggtatactc cgcggttcac 540 caattcccaa ccacaacata cgggcgagac aaggctgcac gcaacccggc acgcgcatgt 600 cgcaggacac gtcacggagc caagaacggg cagcaggacc acagagaacc agacgcaggc 660 cgcgcacgtg gagcggaggg gtagaaccga cagccgccgc gccgtgggca gcggccatgg 720 cgcacacggg ccgacacgga agcggagccg cagcgacagc gagcagcacg cggggcgacg 780 gcgcggcgag gaggggagcg gcgcggggaa cggacgctgc agagaggcgg agggcggcga 840 gccgcggcgc ggccgagccg aaggcgaccg caagcggcgg cggcggc 887 142 2086 DNA Homo sapien 142 cgagccaaga attcggcacg aaaaacaaat acttcctgat cgatcccttg tcttgtttag 60 tatgcttcct gaccattttt taccctaaca tttgtgttct tttcccgaga aggaaaatca 120 acttctatcc tatctctacc cagcagaggc ccctgcccca ctttacacac aaaaccatct 180 aactttttga tattctaaat gggggaaacc cctattttat aaccctcggt tacttttaat 240 ctttagatga ggaactagag gagccactat gttcctctca gcaccatgat ttatgcctta 300 gctaaggcct tcacttgggg aaggggaaga aggttgtttt caagcctgtg gcctcctgtc 360 actccccacc cctggaaggc ccttcacttt tgggtgatgc ctagaggcct catggacagc 420 agtcccttct gacacccagt gagatatcat ctgggagggt cgcagccctc agttcccctc 480 atggctctct ctttcacttc cctccatgac accacctcat cgagttgaag atgttattga 540 tgagtgcagt gggtgtatag tgtcctccca aaattcatgt ccacccagaa attcagaatg 600 caaccttatc tggaaataga atctttgcaa atgtgattag ttaagatgaa atcatactga 660 gttaggatga acctgaaatc caatcactgg tgtccttgta agaggaaagg tcacaaagag 720 acagaggaga tacacagagg agcccatgta atgatgggta cggagactga cgtggcacaa 780 ctataagcca aggaatgcca gggaaggcca gctagcagaa gctagggaaa aacacagagg 840 gattctcccc tggagccttt ggagggagtg tggccctgct gacaccttgg ttctggactt 900 ctggccccca gaactgtgag aaaataaatt tctgtggttt aagccacaca gtttgtggtg 960 ctctgacttc gtgagctttt ctgcccatct gacagcgcct gcctgccttc ctccctgccc 1020 accgtcctcc cgccccgtcc cagaccctcc tcgctcctca tcccactcca ctcctgtgag 1080 tgctcctcca caccatggct gcaatcccca ccttaagctg gggactccca aaccccgact 1140 tccccacagg gctcaggagg cctttctcca gccagcctca catttggact catgcttctc 1200 ccccatgcca ccctcagcta cgctgaatta ttcacagtaa tcgcttggtt ggggaaaagg 1260 ttagtaaatg ccaaaggaaa tacccacaga aatctcctac acagcttaga tgttgtgctg 1320 gcatttaagg cccatgagtg atggtccatt ctgcagcttt tcatgccatg cctttccttt 1380 gtgtgggggt ccacagatca gagtctgtct gtggcatcga cttccttatg tcctcattgt 1440 tcccacccat tgctgggatg tccacgttgg acttctcaaa agtggccaag aatctaagtg 1500 caaaatctgt ttggattttt acaatttttt cctaatcttt tacagtcttg gtcattccta 1560 tttcaactgc aatttttttc aatgacttgc ctggtgtgaa tattttttta aagcatccag 1620 tattaaacaa aaaaatttaa acagctaaaa aaaaaaaaca aaaaacaaac ggctgggcga 1680 aaccagggct caataccggc tccccgtggt gctgaacact ggtatactcc gcggttcacc 1740 aattcccaac cacaacatac gggcgagaca aggctgcacg caacccggca cgcgcatgtc 1800 gcaggacacg tcacggagcc aagaacgggc agcaggacca cagagaacca gacgcaggcc 1860 gcgcacgtgg agcggagggg tagaaccgac agccgccgcg ccgtgggcag cggccatggc 1920 gcacacgggc cgacacggaa gcggagccgc agcgacagcg agcagcacgc ggggcgacgg 1980 cgcggcgagg aggggagcgg cgcggggaac ggacgctgca gagaggcgga gggcggcgag 2040 ccgcggcgcg gccgagccga aggcgaccgc aagcggcggc ggcggc 2086 143 676 DNA Homo sapien 143 gccgccgggc aggtactaaa taaaatgcaa aacatgtcac atcactcttc ttcatgggtt 60 catgtcctct gtgggtcagg tcttccacat gtagagtaga ggtagggtat gttcacacct 120 tcaatgacaa cctacacatt tctgctccaa caggtccaaa attgttccta ggtttcaaag 180 ttgttgtttg tttgtttttt tcctttttct tttttttttt tttttttgga gaagtggagt 240 ttggctctgg ttggccccgg tgtggagtgt gcaaggggcg gtgatctgcg gttcaccaac 300 aaacctcgtg gtcctccgcg gtttacaagg gcgattattc cgtggcctac aggcctcgcg 360 agtatagccg tgggatataa tagggcagtg gcgcacacca gtgcccgagc ttaatttgtg 420 ggtattttaa ggtagaagaa gcggggttct ctcccccctt tgtgtgggtc tcgagggcgt 480 ggactctggg aggcctcgcg tggaaccctc gaggggtgat ctcacacctg tgcgcttggg 540 ggccttccca caaaaggtgg gcctgggggg atttaccagg gcgtggcaga agcccaaact 600 atgtgggccg gggcgcacac aggggggttt cccaaaaggg tttttttaac cggtattaaa 660 aagagggttt cgctag 676 144 1260 DNA Homo sapien 144 taaacataca cacatcaaaa ataactcagc cacatgcaac aatacagaga atcttaaaga 60 catagtatga gcaaaataat cagtacacac aaaattccac ttatacaaag ctcaaaaaca 120 aaattaagca atatttttta gaaatgcact tataaatgat gactgaccca ctatcaagga 180 aagtatttaa cattgctctg aaagttctgg aaattcttga ttttcctttc tcaatttcta 240 cacccatcac cacgcccagt cttccccaac tcactaaaca gcaccgtcat ccatttagca 300 tttcaagcca gtgagaagtc atccttaatt ctgctttttc attaatttcc ctacttctaa 360 tctattacgt gtcttattag atctaagatc aatatatttc ctgaatatgt ctatttatgt 420 ccatttccaa cactaccact gaagtctaag ccattgtcac ctttctttct ggattactgc 480 aatagcctca cagcttccac tcttgaccac atacactcca ttctgcactc agccctcata 540 gtgatcatta taaaggataa aatggtgtgg ccagttagct cagttggtta gatcatggta 600 ctaataaaat gcaaaacatg tcacatcact cttcttcatg ggttcatgtc ctctgtgggt 660 caggtcttcc acatgtagag tagaggtagg gtatgttcac accttcaatg acaactacac 720 atttctgctc caacaggtcc aaaattgttc ctaggtttca aagttgttgt ttgtttgttt 780 ttttcctttt tctttttttt tttttttttt ggagaagtgg agttttggct ctggttggcc 840 caggcgtgga gtgtgcaagt ggcggtgatc tgcggttcac caacaaacct cgtggtcctc 900 cgcggtttac aagggcgatt attccgtggc ctacaggcct cgcgagtata gccgtgggat 960 ataatagggc agtggcgcac accagtgccc gagcttaatt tgtgggtatt ttaaggtaga 1020 agaagcgggg ttctctcccc cctttgtgtg ggtctcgagg gcgtggactc tgggaggcct 1080 cgcgtggaac cctcgagggg tgatctcaca cctgtgcgct tgggggcctt cccacaaaag 1140 gtgggcctgg ggggatttac cagggcgtgg cagaagccca aactatgtgg gccggggcgc 1200 acacaggggg gtttcccaaa agggtttttt taaccggtat taaaaagagg gtttcgctag 1260 145 433 DNA Homo sapien 145 cggccgccgg gcaggtactg gtggttggtt tcattagtgg atcacacaca gggttgtact 60 tggcttgtaa aatggtgcct cggatagggt gagtttggat aagtatgtat gtatgtatga 120 gttatagcaa aattaagtag attgaatcaa gtccatgcaa aagcagtaaa acagttatta 180 attgttaatt ttttaaaaat taaaacgtta ataaaacagt ttgtaatgtt ttgctagtgt 240 cttttataaa atgatgtaag ttacagtgga agtcttcaca ggacttgtgt ctttcctgga 300 actattgaaa tgtaatttag gatgatttga tcttccatct caagttgtca acatggctgt 360 gtcattctgg cttacatatg ttttatttaa caaaattcta gtcaagggat aaggccttaa 420 tgaagacaag ctt 433 146 1791 DNA Homo sapien 146 ggaatgaaca aacaaacaaa aatccttgct ctcctggtgc ttacatttta gttgggagag 60 ggacaaacaa gataagggaa atacatacct tagttaagaa caagtgccac agaggaaaag 120 ccaggctgag gcagtgggtg tgaacatttt atacagggat gtccagaatc agggctttga 180 agaaagccct gaaggcagcg tgtaccgagc aggaatgccc tgtggaggct gagcatttag 240 gaagtgggaa cagccggtgc ggaggtcctg gagggtgagg ggtgtcaaga aggccagcat 300 ggctggagca gaaagcaggg cggggaggtg ggggaccagc tcacaggtgc ctagagccag 360 aatgagaagg gcttcttggc tggattacag gcgtgagcca ctggaacctg gccttgtttt 420 gctttatttt ttctcttaca tgaagtaaag cgctttggtc aaacacacaa aaatactgcc 480 ttgtactggt ggttggtttc attagtggat cacacacagt gttctacttg gcttgtaaaa 540 tggtgccttg gatagggtga gtttggataa gtatgtatgt atgtatgagt tatagcaaaa 600 ttaagtagat tgaatcaagt ccatgcaaaa gcaataaaac agttttaatt ttttaatttt 660 ttaaaaatta aaactttaat aaaacagttt ttaatttttt gctaggttct tttaaaaaat 720 gatgtaactt acatggaagt cttcacagga cttttttctt tcctggaact attgaaatgt 780 aatttaggat gatttgatct tccatctcaa gttgtcaaca tggctgtgtc attctggctt 840 acatatgttt tatttaacaa aattctagtc aagggataag ggcataatga agacaagctt 900 cagttatgaa agtacaaact atttgtgtga ttaattttta aaaatgacat taagaagccc 960 attgtaaaat aatatttgca gtcaaatggt ttttcttgct gtaagtcctg ttgtagctat 1020 gtttagggta gtggttctca tctaccttgg agtgcataag acttacctag caggcttgtt 1080 taaaaagttc agattcctag ctttgtaccc agggattgcc tcaggtggta tgggctgtgg 1140 tcctggagtc atcactttta taaatagtgg ttcagagacc acagagagag actgcttcat 1200 cgaatgggaa gtaccaagga gaaagtacaa ttcagtattg tctggaggca agtggacact 1260 ttgtacctga ggtttagaat aggtggtctc ttgccagtac aatccccagg cgttttctgt 1320 gttcagaagt agtaagaatg cctttaattc agaggattat ctaagctctt taaagctgtt 1380 tttctccatt tgtcatagtg ccttctctga aaaatgaatg tacaggtatc ctattttcta 1440 atgtaattag gattttttaa aagcaatttt gatagttttt cttttaaaaa gtaaaattca 1500 gcactgtgac ttgaaccccc aaatctttca catacaggtg aaacattaag ccacaaataa 1560 atatgacaga aagaagaaaa gatcctattc ctgtcattag ggactagtac ccattaactt 1620 gaaccgactc ggcaaggttg caacatttct tggcacatcg tgcacacact atgttttgac 1680 acgaggactt cccacttata aacaccggac cggggaatat ttcacatcgt ttaagtaatg 1740 caccccgggc aaaaaggaga aaccctcatt caaaaaatct atcgccgtct a 1791 147 349 DNA Homo sapien 147 ggaatgatcg atactatagg ggcatggttc atctaatgca tgctcgagcg cgcgccagtt 60 gtgatggatg cgtggtcgcg gccgaggtcc acgtttagct gagtataatt ttaaatagcc 120 ctatgtgaca agtggctact ttattggaca gtgtagatct aagattaatt cctcaactgt 180 tttgcactca acaaagacat acctctgagt tggcaaccag cagggtggat aacgggccag 240 tggtgataaa atcaaagaat aggtaatgaa acaatcatcc agttaacaat cagcaaggtt 300 cttcagagcc taattaatgt ttaattctaa ataaattgca acaattaag 349 148 848 DNA Homo sapien 148 agctgggatt acagacgccc accaccacac ccagctaatt tttgtatttt tagtagagat 60 ggggtttcac catgttggcc gggctggtct tgaactccta acctcgtgat cctcctgcct 120 cagcctccca aagtgcaggg attacaggtg tgagccactg cgcccgacat cccatttaac 180 tttctgtctc tgtgactctg atgactctag gaacctcata taagtggaat aatataggat 240 ttattctttt ttaaaaaatt tattttgaga tggagtctca ctctgtcact caggctggag 300 tgcagtgact cgatctcggc tcactgcaac ctccgccttc ctggcttaag caatttttgt 360 gcctcagcct cccaagtatc tgagattaca ggcgtgtgcc accacaccca gctatttttt 420 attttttatt tttagtagaa gatggggttt cgccatgttg gccggactgg tctggaactc 480 ctggcctcaa gtggtcctcc cacctcggcc tctcaaagtg ctgggattac aggcgtgagc 540 caccacgttt agctgagtat aattttaaat agccctatgt gacaagtggc tactttattg 600 gacagtgtag atctaagatt aattcctcaa ctgttttgca ctcaacaaag acatacctct 660 gagttggcaa ccagcagggt ggataacggg ccagtggtga taaaatcaaa gaataggtaa 720 tgaaacaatc atccagttaa caatcagcaa ggttcttcag agcctaatta atgtttaatt 780 ctaaataaat tgcaacaatt aagaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 840 actcggtc 848 149 414 DNA Homo sapien 149 cagtggtacg cgcgacgcag gtaccacagc tcccagtgcc cattacctct atcatggatg 60 ctgggtgact ttgggaagtc accacctctt cccaagcctg tttcccatat cacagatgtg 120 gggccatggc ctcgatgatg gtctccacag gtctttccac ctctgtgagt ccaagtcagg 180 tcaatcagca aggacccaat ctctgaccct gggtcagctc ctcagaacca acccccagca 240 tctctaaagc aaaagcctca cctcaagggc tgctcagaag agagcacctt cagcatgagt 300 tgttgctgga aggatctaat aagctgtgtt tcctgggaag tggtgcttta cttagccctg 360 tggacaactt ctctatgcat ctgtgtgagc agatgatcat tgtattacct ttta 414 150 2088 DNA Homo sapien 150 ggtggcagtg atacatgttg gcaggctggt cttgatcctg actcaagtga tccgccgcct 60 caacctccca aggtgctggg attacaggtg tgagccacca cacttgtgca gtatatcctc 120 agtatgaaga tatttttatc ttcctgtgtt ctctggcttc agagtttcac ctgcccacac 180 agggtccgtt gctggcaact ggacttcccc ataagccttg ggtatcctgt gatgggctgt 240 gtctccctga agattgtctg gcttgcccac ttctccgtgc atgactctgg gtgtgagtct 300 gtctaggaac aggagggaaa gttggactca gacagaaatc agatgcttcc atgtattcag 360 ggcgcgcatt gtgagcagtg gagtatgagc cttgagggcc tcatggttgc agggcaggct 420 tccctgcaga tgggtggcag cccctggtag aatgctggat ttctctggaa tctagaagtg 480 ccatatttta gtggaaaggc atcagggctg tttgacagtg tgcgtctttc caatcccatg 540 ttcctccatt cgtgtgtctg ttataaaact gagtgaaggc tgctatgacc tgtgttcact 600 ctggttacag ggaggtgcaa accattctgt ctcccagcct ttcttctctc tttgtgtgct 660 cccagcactt ccttcttttc taacatggcc tggagagagt ctctctctcc ttgtctctgt 720 ctcttaataa tagtttttaa cgtggacatc tcttccttgg tacagtggtt tttaaatcct 780 gagaagaacc aagtcaggtt ttttaaagca gactaaaagc atgaaattgc tttcagaaga 840 atgtatatca tcgggaaaag tttgggggca gagtggggga atcaggcttt attcaaaaga 900 aacagttgaa aacatggact ttttctaccc aatgcccatt tcacgactcc tctgagacta 960 attgggaaac ggggaaattc ttggaatttt ttttttaaga aacttttttg tgtttttttt 1020 aattttaggt cacttattag tgaaacctca ttttagatct gacattggta gatagatgga 1080 tttaggcaaa tatgatgcgt ttgtggggaa tccacgtggt tgacgttaga acctcccttc 1140 tgcagactgt tgcctgtcat ctaagcgaat tggaaatgct gagcttccat aagtcagctg 1200 agttttaaag gtaaacgtta tggctgaagt agtaaagcac ctgaccacaa aacctcttgt 1260 aaaaacagcc ctgagtaggt atttccaggg ctccacaaag ttgcttatgg gaatcctgag 1320 ctgcttttca ccatctcaag aagcctaaga agttatatat ttaatcaggt agacaaaaca 1380 gttcaaagca taaggtccat ggtggtggaa aatggatgca agtgattcta agtttgtgga 1440 tttgtggata gcagagggat cgggacctct tggaggaacc ctgggtacca agctcccagg 1500 cccttcctct atcatggatg ctgggtgact ttgggaagtc accacctctt cccaagcctg 1560 tttcccatat cacagatgtg gggccatggc ctcgatgatg gtctccacag gtctttccac 1620 ctctgtgagt ccaagtcagg tcaatcagca aggacccatc tctgccctgg gtcagctcct 1680 cagaaccaac ccccagcatc tctaaagcaa aagcctcacc tcaagggctg ctcagaagag 1740 agcaccttca gcatgagttg ttgctggaag atctaataag ctgtgtttcc tgggaagtgg 1800 tgctttactt agccctgtgg acaacttctc tatgcatctg tgtgagcaga tgatcattgt 1860 attacctttt atcggtagta agcttggaaa aataatttaa gaatacaatg gagaaatgta 1920 aataagtatc tatgtaaatt tgtttaaaat aaactgaatg tatttaatgg tccatttata 1980 tgttctttta tgtaacatgt agtttaataa agttcctgtt tatgagagtc atgtttcatc 2040 tcagcttctt ccaaaaaaaa aaaaaaaaaa agatctttaa ttaagcgg 2088 151 509 DNA Homo sapien 151 cggactcccc ccgcggacgc gctggcttcg cgtatcggtt tacttccttt ataaaaattt 60 ttataactta tgtggaaatg ggatctcact atgttgctca gacttgtctt gaactcctgt 120 tatagcacca cctcttacaa gtgttgggca gctccgcttc tctcacttgt ctggaattct 180 aaggcacttc cctgaagtgc tcatcctgag ctaatatggg atagggctgg agagagaaca 240 gaggtggata gcatgccaga atgaggtggg aaggtgggga tcagcagcct ttgggaagga 300 aagaagtatg agtcccaggg tattaacaag gtggaggggc aataaaattt attacatatt 360 gggattcata ctaaatgagt agattttagc ttctcttgcc acaataaaca aaaaaaatgc 420 cacaacacca cacaaaaaaa aaaggtgcgg ggaaccaggg ccaaacgtcc ccgggtgaat 480 gtttcccgcc atcaaattaa aacacacag 509 152 560 DNA Homo sapien 152 ccagcctggg taacagatgt gagaccctgt ctgttaagag aatcagaaaa gagagagaaa 60 gctagactta gctccaagtc tggagctttt ggggttttct tcctttataa aaatttttta 120 acttatgtgg aaatgggatc tcactatgtt gctcagactt gtcttgaact cctggttagc 180 accacctctt acaagtgttg ggcagctccg cttctctcac ttgtctggaa ttctaaggca 240 cttccctgaa gtgctcatcc tgagctaata tgggataggg ctggagagag aacagaggtg 300 gatagctgcc agaatgaggt gggaaggtgg ggatcagcag cctttgggaa ggaaagaagt 360 atgagtccca gggtattaaa aggtggaggg gcaataaaat ttattacata tgggattcat 420 actaaatgag tagattttag cttctcttgc cacaataaac aaaaaaaatg ccacaacacc 480 acacaaaaaa aaaaggtgcg gggaaccagg gccaaacgtc cccgggtgaa tgtttcccgc 540 catcaaatta aaacacacag 560 153 577 DNA Homo sapien 153 tgatgatata tggggcatgg tcctctagat gctgctcgag cggcgcagtg tgatggatgc 60 gtggtcgcgg cgaggtacca cctgttcatt ggggaactgt gggaaacgga gccaacggac 120 ctaagtgccc tttgacagtg agtttcatac catttcagta gtgtatttct ttcttaatct 180 gaataaacca gtatgatact ctcagacaca gaagaataaa gggagcgagt cattaacgtt 240 ttctttttaa acctttatga tgacttcctt atgaattact gaacgaacac tggaatggga 300 ctcaggtatc ctgaggacat ctctcaactc tggccttagt tccccctctg taaaattagg 360 gtgccaacta aatgatctac aaggtccctt ccagcgccgc cattctgtaa ttacatcatg 420 tgtaactgta ttaaacatac acaagtgact gccaggcatg ggaatgtaac ttccgagtaa 480 atgctttggt ttgttcagaa tacactatga acttctttcc aaagacgggt tgtggtaaat 540 agtggatatt ttgattataa gaaatagagt ttccttg 577 154 1138 DNA Homo sapien 154 aagaaattcg gcacgaggaa agtgctggga ttacaagcat gagcccagcg cctggctgta 60 tctttcattt tacccaagtc actttaccca agtaagtaat taggggaaag cctgagtctt 120 gtaccacctg ttcatttggg gaactgtggg aaacggagcc aacggaccta agtgcccttt 180 gacagtgagt ttcataccat ttcagtagtg tatttctttc ttaatctgaa taaaccagaa 240 tgatactctc agcacagaag aataaaggga gcgagtcatt aacgttttct ttttaaacct 300 ttatgatgac ttccttatga attactgaac gaacactgga atgggactca ggtatcctga 360 ggacatctct caactctggc cttagttccc cctctgtaaa attagggtgc caactaaatg 420 atctacaagg tcccttccag cgccgccatt ctgtaattac atcatgtgta actgtattaa 480 acatacacaa gtgactgcca ggcatgggaa tgtaacttcc gagtaaatgc tttggtttgt 540 tcagaataca ctatgaactt ctttccaaag acgggttgtg gtaaatagtg gatattttga 600 ttataagaaa tagagtttcc ttgaagcttt agctggagat acagcaatag tgtggtgttc 660 ctacaaatat cacagtgtat tcaaacatat ttttctatca aaaatcattt ttgtaaaagc 720 tgtgtgtttt tatccaactt gtgataataa atgttcttta ttttagaata aaaaaaaaaa 780 aaaaaaaaaa aaagaaaaaa aaaggaaata aaaaaaaaaa acaggagaca aagacaacgg 840 cggcacgcaa caaccacatc gcggaaggcg acaagcgaac aacccagccc gagctcgtga 900 aggcgagcca acatgaagga gcgcactatc caagacaggt agctgacata acagaagaga 960 acaaaaacaa gagacaagta gaacaaaaac aaagagaaga caggacacac gagaaaagca 1020 ggtgtaatca gacgaacgac gcgacaaaca gagagacgtg caagcataaa atagcaacaa 1080 ccaagagaca gcgacggaca cacgaagcaa gacgagcgac gccgagcaca gcagggat 1138 155 800 DNA Homo sapien 155 cgtggtcgcc ggccgaggtt gccataggcc ccagaccaaa ctagaccacc agcatgttca 60 tgtccagacc tcggcagtgg cgtgcactgc ttgtgcacct cagttcctcc agtgttggtt 120 tgtttgtttt ttaattcagc atcctgctgg ttttactttc caagcaagat ctgttgcgac 180 tcccaaatgc gttttaatga gctcatcctt atttgccttt cttcttacgt attttgttgt 240 atttaaagat tgtgcaggag atattctaga aggcattaat ggtttgcatt caaaacgatg 300 tggtttgtcc aagttatttt ctgtctttat tactgagacg gattaatctc cttatttttt 360 tcttgatgat ttgaagttgt aacagttgtc cagctattgc ttaataaaat tttgcagatc 420 aaaaaaaaaa aaaaaaaaaa aaaaaaggtt gggggtaacc agggccaaga ggggtccctc 480 ggggtcgaca attgggtcac ccgggtccat caatttcccc acaaacataa tacaggacat 540 aggcacacac agcaaacgca cacagcacca agacagacaa ctacggcgag ctaaggacgc 600 agagaagacg cggcaacgcg gaacgccccg agcaaggccg aggcaacaca ggagaggggc 660 agcgcacgac ggccggagca cgagcaggaa agcaacgaag agagacaacg gacacacgcg 720 agggcgaaga gaagagagca ggaacgacag gacaagcaca caaacgagcg gcaacagcag 780 acccagacga aacagcgcga 800 156 4632 DNA Homo sapien 156 atgtatgcag cagtggaaca tgggcctgtg ctttgcagtg actccaacat cctgtgcctg 60 tcctggaagg ggcgtgtccc caagagtgag aaggagaagc ctgtgtgcag gagacgctac 120 tatgaggaag gctggctggc cacgggcaac gggcgaggag tggttggggt gactttcacc 180 tctagtcact gtcgcaggga caggagtact ccacagagga taaatttcaa cctccggggc 240 cacaatagcg aggttgtgct ggtgaggtgg aatgagccct accagaaact ggccacgtgc 300 gatgcggacg gaggcatatt cgtgtggatt cagtacgagg gcaggtggtc tgtggagctg 360 gtcaacgacc gcggggcgca ggtgagtgat ttcacgtgga gccatgatgg aactcaagca 420 cttatttcct atcgagatgg gtttgtcctg gttgggtctg tcagtggaca aagacactgg 480 tcatccgaaa tcaacttgga aagtcaaatt acgtgtggca tatggactcc tgacgaccaa 540 caggtgctgt ttggcacggc cgatgggcag gtgattgtca tggattgcca cggcagaatg 600 ctggcccacg tcctcttgca cgagtcagac ggtgtcctcg gcatgtcctg gaactacccg 660 atcttcctgg tggaggacag cagcgagagc gacacggact cagatgacta cgcccctccc 720 caagatggtc cggcagcata tcccatccca gtgcagaaca tcaagcctct gctcaccgtc 780 agcttcacct cgggagacat cagcttaatg aacaactacg atgacttgtc tcccacggtc 840 atccgctcag ggctgaaaga ggtggtagcc cagtggtgca cacaggggga cttgctggca 900 gtcgctggga tggaacggca gacccagctt ggtgagcttc ccaatggtcc ccttctgaag 960 agtgccatgg tcaagttcta caatgttcgt ggggagcaca tcttcacact ggacactctc 1020 gtgcagcgcc ccatcatctc catctgctgg ggtcaccggg attcgaggct gttgatggca 1080 tcaggaccag ccctgtacgt ggtgcgtgtg gagcaccggg tgtccagcct gcagctgctg 1140 tgccagcagg ccatcgccag caccttgcgt gaggacaagg acgtcagcaa gctgactctg 1200 cccccccgcc tctgctccta cctctccact gccttcatcc ccaccatcaa gcccccaatt 1260 ccagatccga acaacatgag agactttgtc agctacccat cagccggcaa cgagcggctg 1320 cactgcacca tgaagcgcac agaggacgac ccggaggtgg gcggcccgtg ctacacgctc 1380 tacctggagt acctgggcgg gcttgtgccc atcctcaaag ggcggcgcat cagcaagctg 1440 cggccagagt tcgtcatcat ggacccgcgg acagatagca aaccagatga aatctatggg 1500 aacagcttga tttctactgt gatcgacagc tgcaactgct cagactccag tgacattgag 1560 ctgagtgatg actgggctgc caagaaatct cccaaaatct ccagagctag caaatcaccc 1620 aaactcccaa ggatcagcat tgaggcccgc aagtcaccca agctgccccg ggctgctcag 1680 gagctctccc ggtccccacg gttgcccctg cgcaagccct ctgtgggctc gcccagcctg 1740 actcggagag agtttccttt tgaagacatc actcagcaca actatcttgc tcaggtcacg 1800 tctaatatct ggggaaccaa atttaagatt gtgggcttgg ctgctttcct gccaaccaac 1860 ctcggtgcag taatctataa aaccagcctc ctgcatctcc agccgcggca gatgaccatt 1920 tatctcccag aagttcggaa aatttccatg gactatatta atttacctgt cttcaaccca 1980 aatgttttca gtgaagatga agatgattta ccagtgacag gagcatctgg tgtccctgag 2040 aacagcccac cttgtaccgt gaacatccct attgcaccga tccacagctc ggctcaggct 2100 atgtccccca cgcagagcat agggctggtg cagtccctac tggccaatca gaatgtgcag 2160 ctagatgtcc tgaccaacca gacgacagct gtagggacag cagaacatgc aggtgacagg 2220 tgccacccag taacccaggt ctccaaccgg tactccaatc ctggacaggt gattttcgga 2280 agcgtggaaa tgggccgcat cattcagaac ccccctccac tgtccctgcc tcccccgccg 2340 caggggccca tgcagctgtc cacggtgggc catggagacc gagaccacga acacctgcag 2400 aagtcagcca aggccctgcg gccaacaccg cagctggcag ctgaggggga cgcagtggtc 2460 tttagtgccc cccaggaggt ccaggtgacg aagataaacc ctccaccccc gtacccagga 2520 accatccccg ctgcccccac cacagcagca cccccgcccc ctctgccgcc cccacagccc 2580 ccagtggatg tgtgcttgaa gaagggcgac ttctccctct accccacgtc agtgcactac 2640 cagacccccc tgggctatga gaggatcacc accttcgaca gcagtggcaa cgtggaggag 2700 gtgtgccggc cccgcacccg gatgctgtgc tcccagaaca cctacaccct ccccggcccg 2760 ggtagctctg ccaccttgag gctcacggcc actgagaaga aggtccctca gccctgcagc 2820 agtgccaccc tgaaccgcct gaccgtccct cgctactcca tccccaccgg ggacccaccc 2880 ccgtatcctg aaattgccag ccagctggcc caggggcggg gggctgccca gaggtccgac 2940 aatagcctca tccacgctac cctgcggagg aacaaccgtg aggctacgct caagatggcc 3000 cagctggccg acagcccgcg ggcccccctg cagcccctgg ccaagtccaa gggcgggccc 3060 gggggggtgg tgacacagct cccagcgcgg cccccacctg ccctgtacac ctgcagtcag 3120 tgcagtggca cagggcccag ctcacagccc ggagcctccc tggcccatac cgccagcgcc 3180 tccccgttgg cctcccagtc ctcctacagc ctcctgagcc cacccgacag cgcccgcgac 3240 cgcaccgact acgtcaactc ggccttcacg gaggacgagg ccctgtccca gcactgtcag 3300 cttgagaagc ccttgaggca ccctcccctg cctgaagctg ctgtcaccct gaaacggcca 3360 cccccttacc agtgggaccc catgctgggt gaggacgttt gggttcctca agaaaggaca 3420 gcacagactt cagggcccaa ccccttaaaa ctgtcctctc tgatgctgag tcagggccag 3480 cacctggacg tgtcccgact gcccttcatc tcccccaagt ctcctgccag ccccactgcc 3540 actttccaaa caggctatgg gatgggagtg ccatatccag gaagctataa caacccccct 3600 ttgcctggag tgcaggctcc ctgctctccc aaagatgccc tgtccccaac gcagtttgca 3660 caacaggagc ctgctgtggt ccttcagccg ctgtacccac ccagcctctc ctattgcacc 3720 ctgcccccca tgtacccagg aagcagcacg tgctctagtt tacagctgcc acctgtcgcc 3780 ttgcatccat ggagttccta cagcgcctgc ccgcccatgc agaaccccca gggcactctc 3840 cccccaaagc cacacttggt ggtggagaag ccccttgtgt ccccaccacc tgccgacctc 3900 caaagccact tgggcacaga ggtgatggta gagactgcag acaacttcca ggaagtcctc 3960 tccctgaccg aaagcccagt cccccagcgg acagaaaaat ttggaaagaa gaaccggaag 4020 cgcctggaca gccgagcaga agaaggcagc gttcaggcca tcactgaggg caaagtgaag 4080 aaggaggcta ggactttgag tgactttaat tccctaatct ccagcccaca cctggggaga 4140 gagaagaaga aagtgaagag tcagaaagac caactgaagt caaagaagtt gaataagaca 4200 aacgagttcc aggacagctc cgagagcgag cctgagctgt tcatcagcgg ggatgagctc 4260 atgaaccaga gccagggcag cagaaagggc tggaaaagca agcgctcccc acgggccgcc 4320 ggcgagctgg aggaggccaa gtgccggcgg gccagtgaga aggaggacgg gcggctgggc 4380 agccaaggct tcgtgtacgt gatggccaac aagcagccgc tgtggaacga ggccacccag 4440 gtctaccagc tggacttcgg ggggcgggtg acccaggagt ccgccaagaa cttccagatt 4500 gagttagagg ggcggcaggt gatgcagttt ggacggattg atggcagtgc gtacattcta 4560 gacttccagt atccgttctc agccgtgcag gcctttgcag ttgccctggc caacgtgact 4620 cagcgcctca aa 4632 157 998 DNA Homo sapien 157 tgctgctcga gcgcgcgcag tgtgatggat ccgcccgggc aggtaccttt tcctctcaca 60 ttggcagaat agcacgcact agatgcctga ccttgagctc tagtctcccc gtttaaatct 120 taccttgggc agtaacgaca attattcctc attcaagtaa tttcaatgct gaaactgaac 180 tctattacta atgccttcca atcagagttc ctgatgggga tgcctgtggg atggcccact 240 aacctggggg acctaggcta gcatggggtg agttgggtaa ggaagatgat gcgttagttc 300 ctgatagatg ctacgagatg tagtttggca tttcagttgt tgtccagtta tgattttcac 360 tgggggttct gcagtcacag caagctgtgt atgaactagc tgtactagtg gatgacacac 420 tataactaat caaactagac taaagacaca ctgaaaatct gcgttataac taacaagata 480 tcactcatct gacacataac caccattaca ccttatggta cgtcaggatt cataaatagt 540 actgctctga atgacttatg ggaaatggtg ccactcaaaa gcaacttcct aacttgagga 600 ataactcctt tgtagtttac tttctggtac tggttggtgc cttgtatcgg gatacagcta 660 tattcttagc tcaaatgtct cttttggaga gcacagtagt tatcctactg gtgagactga 720 gaacctgagc tcatgagagg ccattccttc ctgggtgtcg gaccagggct ctgtgtcagg 780 aaaaaccttc tgggtgacct ttgtagactc gtttcaggtt gattccctct tatcttgcga 840 gagtagaatt cgcagtcggt ggcctttccc ttcacccgta actcggcccc tctgggcagg 900 ggcggggtgg cggctcttaa cgctggctcc gggtttgggg ggcccggggc ccgcaacgcg 960 ggttttgggc gggtcgcgcc cctccctcca acgggccg 998 158 766 DNA Homo sapien 158 gggatgatcg ctcactatag ggcgctggtc actagatgca tgccgagcgg cgccaggtga 60 tggatcgagc ggccgcccgg gcaggtacat gttcatgaat ttgtgctgaa taattacttg 120 agtgtgaaat tgttatgtta tgcgatatat agtagtcaaa tatagaagat aatgcaaaac 180 aatttaaagt gattgtagca gttcgctgta ttctacagca gcaggattgt aggcagatta 240 ctgtagttct cacagcgagc agcatgtgag attggccagt ccgctcaaat tcgtgccaat 300 acttggtata tgctatcttg tcaatttcta gacattctgg agagtgtgta gtacttgttc 360 atcttggaca aattacactt aatagttatg tatccatttc tctaattttg ataacatttt 420 acataagttt atcgttatga gatatgttct ttattttgaa gtgcttattg tccattttac 480 attgggtcat ctgttattga attgtaaaca ttccttgaat atttaaatat gagtgcttgg 540 tcagttttgg tcacaaatat cctcgttttt tcactttttg cccttttatt attctgaaaa 600 tgccaagtga ttaaaattaa ttttactatt gttcaataaa caaaacaaaa aaaaaaaaaa 660 aaaaacacaa aaaaacaaaa gcgcgggggg taaccggggg cccaaggggg tccccggggg 720 acattggtct ccccggtcac aattcccccc aatcgcacaa cagggc 766 159 1400 DNA Homo sapien 159 ctatgattag cttattaggc tttgtggttt atatgcatca gaaagagtaa gacttaattt 60 tgtgtggaac aaataccctg gtgtagcatg tttcattaga atttgtttat agagatattg 120 ccatagaaaa gttatttttt attagtaaag aatgctttgt atttcctttg tggcttctaa 180 gtaccctttt ttggttatta tacctttatc cataagtatc tttaaatatt acaaaaatta 240 catattcttt taaatatttt aaagatttat tatattcatt taggttttaa tccactttta 300 attttttaga tgaaaagtaa gagaaaagta tataaatcat gagcacaaat tgaactaacc 360 aaggtaacaa tcaatctgct caagaaattg agcatcacca ccacctcctc ctgcactgtc 420 caaatcagca ccccagtact ccaaagcaaa tgttactcac tacactgact tctaacacaa 480 tagacttgtt ttgtctgttt tcaactatac aaaaatgaat catagagtat gtgttgtttt 540 gtatctggct cctttcacta aaattttggt ttataaaatt catccatgtg gttgaacaca 600 gttgtagatt gttcatttta attgttttac agtatttatt gtgtgactaa aacactactt 660 atttattcta taattgacag actttgggtt gcttttgctt tgggagtata aacattttta 720 tatctatgct ttaggtacat gttcatgaat ttgtgctgaa taattacttg agtgtgaaat 780 tgttatgtta tgcgatatat agtagtcaaa tatagaagat aatgcaaaac aatttaaagt 840 gattgtagca gtttgctgta ttctacagca gcagattgta gcagattact gtattctaca 900 gcagcagcat gtgagattgc cagttgctca aattcgtgcc aatacttggt attttttatc 960 ttttaatttt agacattctg gagagtgtgt agtaattttt catcttggaa aattacatta 1020 aattagtatc catttctcta attttgataa cattttcata agtttattgt tattagatat 1080 tttctttatt ttgaagtgct tattgtccat tttacattgg gtcatctgtt attgaattgt 1140 aaacattcct tgaatattta aatatgagtg cttggtcagt ttttgtcaca aatatcctct 1200 tttttcactt tttgcccttt tattattctg aaaatgccaa ttgattaaaa ttaattttac 1260 tattgttcaa taaacaaaac aaaaaaaaaa aaaaaaaaac acaaaaaaac aaaagcgcgg 1320 ggggtaaccg ggggcccaag ggggtccccg ggggacattg gtctccccgg tcacaattcc 1380 ccccaatcgc acaacagggc 1400 160 556 DNA Homo sapien 160 acctattcac cattccaacg tgaagaagct ctgcatgtag gaaagaataa ttaacacact 60 tatagtctac tgcccatgta aggatcagct ccggctaaga ggccaaagat gggtgacatc 120 gtcatgctct gccttttatt ttttctttct tacccactta gcttcctaat tggaggaagg 180 aggcgtggta aaggtatatg aagactatgg tttaattaga ccagaaaaca ctgtcataat 240 ctctgggcgt cagtcagaat gtccagtttt gtctttgggc caagataagg gcagtgggat 300 ttatgatgtg ttgtttatag tctgaaacta ctctggtgat caccagggtc agtttcttta 360 atcgatggtt tccaagctgg cctaagtaca tttaagtaga gactgggctg ataaacatga 420 ccagacgaga cataaagacc ctgttgggaa tgacattgaa ctctcaaagt caagatttct 480 tacacaaatc tatcagctgg agaataatga gaggcagctg tggtatatgt gtgcaaataa 540 ggacattatg aagctt 556 161 1327 DNA Homo sapien 161 ggaagacctg attgggaata gtcgaaagcc ttgatatgtg caaagaaaga accatttgat 60 caacccagtt cttaatacag gatactaact taaaatatag actcaagtta tacgataatt 120 caaacattta ttgtatttat actattctat atgtactttt ccaggaacca ggaatacaaa 180 actgacatgt tctctgtaca gaggctcaga ctagtagaga acagttaggt acgccgttaa 240 ttataaacta atatgtatca tcaattatgg gtttttatgg gggtttggca ggtggaaggg 300 accagggaga gatgatgagt gatgatggtt atgtagtctt taggaggatg caattataac 360 attgctcttc ctttcacgca ccacatgatt tagcaagtac ttcatattgg ctccaccatt 420 aacatggtca atggcttctg gatactcaca gttcaggcac agtttctcct gaagattttt 480 tacctctccc atctttaaga aattgtctgg atgtccatga aagatgctga cacttgtatt 540 aattcattaa aaaacaccac cccctccctg aaataaacta aaaagtaatg aattcataga 600 aaaaaatttc accaagattg aaactagaga atatacctag acttgcactt tgagctttga 660 gaaatgtgta cctattcacc attccaacgt gaagaagctc tgcagtagga aaaataatta 720 acacacttat agtctactgc ccatgtaagg atcagctccg gctaagaggc caaagatggg 780 tgacatcgtt atgctctgcc tttatttttt ctttcttacc cacttagctt cctaattgga 840 ggaaggaggc gtggtaaagg tatatgaaga ctatggttta attagaccag aaaacactgt 900 cataatctct ggggtcatca gaatgtccag ttttgtcttt gggccaagat aagggcagtg 960 ggatttatga tgtgttgttt atagtctgaa actactctgg tgatcaccag ggtcagtttc 1020 tttaatgatg gtttccaact ggcctaatac attaagtaag actggctgat aacatgacca 1080 gacagacata aagaccctgt tgggaatgac attgaactct caaagtcaag atttcttaca 1140 caaatctatc agctggagaa aatgaaggca gtgtggtata tgtgtgcaaa taaggacatt 1200 atgaagctta aatatggaat gtctcttgga cccccgatgt catctgtatt ctctttttct 1260 tcttgtacta tatcctttgc ctgtaaataa aaggtttatt tgaaaaaaaa aaaaaaaaaa 1320 gatcggc 1327 162 318 DNA Homo sapien 162 ggttctccta aatgtcttaa cccatgttta tcttgttctg ctattccatg agcaaagaga 60 ataaagcaca aagctgtgag agtattaaat atggacacta gatttacatt tccaacaaga 120 aattcatctc cctccaaagt cccagaccag ggctagaatg tggttcattt ttaacaatca 180 aagtggcaag atctgtttgg tgatcactgt aaaacaggaa acacagtaat gccttcatgt 240 tgaggtgcta aaaggtcaag cttgggtaac aatgtccata gctgttctgg tgaatgtttc 300 gtcaatcaaa tagtgaaa 318 163 1042 DNA Homo sapien 163 acagtctgtt tcctccttca cccccagaac aaaaatcgaa cttctggttg gacagtgtca 60 gatgtcactg aggtgacccc agcctgtttg cagttccaag tcttccgtgt aggcgtcact 120 gctactggaa ctttgtagat gaggagcctg tatgatgatg tcctgaacat ttctatcctt 180 tcctcacaca gagggaagct actgggaata tcagagacaa gctattatta aacaagtgtc 240 tctagtccaa gacatctcct gtggcaggga aatgaggggg caggctgtat cagtgatatt 300 tttataaact ctggttttag aaaaaattct tcagatggac gcattatttt aagactttaa 360 cattttccaa aaccaactga atcttatccc ctccatttat ccccctccag acacttctaa 420 tcaaggtcac catctccaac ttcccccata gacagtaaaa atatggctgg agaattctac 480 tgtaatagaa aaccaaggag atatggtaat ttgacagtgt gtttcctttc catccactag 540 acaagaatac cccctcccat tctttcctcc cctcagtcac cagaatgaag tgggctggaa 600 aacagttggt ctggttcctt tatagagact gattcccaca ttggatactg cctggaggcc 660 ttggggatga atgagaagtt ctgctggttt ggatcagtag cagaagcagg taacacatca 720 gggaaccggt cagcctaaga taggagggga cagaaaatga tgaaagagtt tctgatacat 780 ttatcagcta aattgctatg gtcaccccca tgtctcctgt aatgtccaac actaaggaat 840 taaactaagt aaactacaac ctttgtgtct tgctctgacc ttggaccaat ggaatatact 900 tcttatttca tattcagtgg ataagcaaat ctgcttcatc cctgccttaa ctcactcaag 960 gtctctgtga tgcactccag agttttcctc cttccctgca tagtcttctc ctccctagct 1020 gcctttcaaa ttggtgaaaa tg 1042 164 1120 DNA Homo sapien 164 gccgcctttt tttttttttt tttttagaca agaaattatt ttagtccttt agtacagtct 60 gtttcctcct tcacccccag aacaaaaatc gaacttctgg ttggacagcg tcagatgtca 120 ctgaggtgac cccagcctgt ttgcagttcc aagtcttccg tgtaggcgtc actgctactg 180 gaactttgta gatgaggagc ctgtatgatg atgtcctgaa catttctatc ctttcctcac 240 acagagggaa gctactggga atatcagaga caagctatta ttaaacaagt gtctctagtc 300 caagacatct cctgtggcag ggaaatgagg gggcaggctg tatcagtgat atttttataa 360 actctggttt tagaaaaaat tcttcagatg gacgcattat tttaagactt taacattttc 420 caaaaccaac tgaatcttat cccctccatt tatccccctc cagacacttc taatcaaggt 480 caccatctcc aacttccccc atagacaata aaaatatggc tggagaattc tactgtaata 540 gaaaaccaag gagatatagt aatttgacag tgtgtttcct ttccatccac tagacaagaa 600 taccccctcc cattctttcc tcccctcagt caccagaatg aaggggctgg aaaacgttgg 660 tctggttcct tttagagctg attccccatt ggatactgcc tggaggcctt ggggatgaat 720 gagaagttct gcagtttgga tcagtagcag aagcaggtaa cacatcaggg aaccggtcag 780 cctaagatag gaggggacag aaaatgatga aagagtttct gatacattta tcagctaaat 840 tgctatggtc acccccatgt ctcctgtaat gtccaaacct aaggaattaa ctaagtaaac 900 taaaaccttt gtgttcttgc tctgaccttg gacaatggaa ttcttcttat tttcattcag 960 tggatagcaa atctgcttct tccctgcctt aactcactca aggtctctgt gatgcactcc 1020 agagttttcc tccttccctg catagtcttc tcctccctag ctgcctttca aattggtgaa 1080 aatgaagctt caggattatg aaaactagta cttaatgaag 1120 165 810 DNA Homo sapien 165 agatcatgct cgagcggcgc agtgtgatgg attggtcgcg gccgaggtac ttttttatgg 60 cttacatctg tgcctggtcg gccatcaagt ctgggtgcca ctgtttgaga tttggggctg 120 tttcctgcaa ctgatctctg ctacagataa ggcttccctc ctggaggcca aagccctggt 180 taacgttaag agctctatga tgatgcaaac ttcagaggcg atcacctaac ataacaaaaa 240 cctccccaga accagaacct gttttttcac caaaaccctt ccgctgcttg aataagaatg 300 tcttttcctt tcctaccaac tttgatgcca ctggccactg tgacataact tttacttagc 360 ggggtaaatc atagatggat tacttgaact gccaacacaa gactgctgga cgagggacag 420 agctggatat gttagacaaa gatatacgaa cgacttggcg taatcactgg tcaatagctg 480 acaccatgat gtgaaaagta gtaatcacgg ctcacaagta ccaacacaag atacagaaga 540 caggagaaga ggaacaggaa aagaagaaac aacagagcac aaagagagaa caagcacaca 600 acagacgaag gccacaagag cgaaggagga ccggacgcag caccagcaac agaggaacgg 660 cacgcacaga agaacacaga caagaaaacg agaagaaacc acacgcacaa ctagccagaa 720 tcagagacag aaaacgcgaa gacaggaggc agaagcagaa acacaagaaa accgaacacc 780 aaaacaggca gcacaaacac gaagagaaag 810 166 601 DNA Homo sapien 166 gaagtataac tatatgggcg aatgggtcct tagatgcagg ctcgagcggc gcagtgtgat 60 ggatccgccc gggcaggtac tcaggtgtta tatgattttc tgagctgaat aagtgcgagg 120 agcagattat taagatctgc cattctgaaa cgctggtctt tttctccttc ctatagtgca 180 ccataaaatt ctgttgatca gattatatta catacatttg ggggagtgga gggacatgag 240 ttaagtagcc cttcatgtat ttataatctc ttttctactg aatcaaatga cttagccatg 300 accctgaatg gacctgtttt acttcaagtg agatgtctgc cttttatgaa ttgtatatgt 360 gaatagagtt cgggggttgc caaaaatgca tacatgtatg taagtaaaat tttttatgaa 420 gtagtctgtc aaatgtatca taaagtttat ttttctttta tacgtaaatc attaaaaata 480 atcacatatt tttgaaaaaa aaaaaaaaaa aaaaaaaggt ggggggtatc tcggggccaa 540 aaggggtccc gggggggaat tggttttccg gttcaaattt ccacaaattt gggagaaaat 600 a 601 167 1035 DNA Homo sapien 167 tggtcgcggc gaggtactgt aaatgtgatg gaaaacattg atgagaattt attggcagtt 60 cagattgtgt tttcccaact taggctcttt attaattggt taaggttttc tccaaaaagg 120 gcatttcaac aatgggaatt attttaaatt ggttaaacca gtgggcacag attacttatc 180 ttccttctct gctttgtgac tcaccagcag taacacacac aatccacatc ttgtgcacct 240 caaatgaaca gacttggttt ccttgctttc ttgacatttc catgactgtt tcacatacaa 300 actattgggt gaggtttttc agctgttacc gacccacgtc ctgctgtctc tgtgtggtcc 360 tacaaaaact gtccattccc acccctttgc tttgccattt gcaagagtct ggaattgtca 420 ggtctcagct tcgaaaagtc ctggttccac tgacaggaca cattctttag tgggaattaa 480 gacctacaaa gtctagtttg tatgtaggta tgaagggaat tttttaaata aagtggaaaa 540 gctgtgaaca gcattagaac tctgtctatt tcttaatttt aaaatatgct gatatgcctt 600 aaactgtagt tgtagatcct tgtcattttg ctgtttgaaa ataaccaatg tgttttctaa 660 aactgtcgtg taatctactt tcattgttaa tgcagaattg tcatatatgt aagccgcatg 720 ttagacattt gtctttttta aactaaagta attgtattga tgtgaagcat atcatttttt 780 caaatatgaa agtgatcact tagcaacatg cttggtaatt tggcatctgt taaggtagga 840 gagtggtgaa cagataatct atgcatatat cactagtgcc aagacataaa gcgggggaaa 900 atatattttt acccaaacat taaaaaaaac aaaaaaaaaa aaaaaaaaaa aaaaaaaggc 960 tgggggtaac cggggccaaa ggggtcccgg ggtgaattgg ttttccgctc aaattccccc 1020 atttttgggc aaacc 1035 168 1666 DNA Homo sapien 168 ctgggtgatg aagtgagact ctccaaaaaa aaaaagaaat tattaatccc tgcctgtgct 60 ctacatagcc tcatgggcat cattggatag ctcagagggc ccttgattct ggcaaggcaa 120 ataaagccag aatgagaaat taccatcttc tactagagaa aaccaagaga aaaattttta 180 tgctaggatg cctttatgac cacttaattt tttaatctta gtttaatggt ctctccctgg 240 tgctaactgc tgacagtggc cacctctttt ttggggattg aggggcctac ataactagct 300 ggccttaccc catatctttt gttcaaacat aataccatct ttttgcttct tctgaacttt 360 agatctccat aacacatgta ctgtagaatg tgatggaaaa gcattgatga gaatttattg 420 gcagttcaga ttgtgttttc ccaacttagg ctctttatta attggttaag gttttctcca 480 aaaagggcat ttcaacaatg ggaattattt aatgtaacag tgggcacaga ttacttatct 540 tccttctctg ctttgtgact caccagcagt aacacacaca atccacatct tgtgcacctc 600 aaatgaacag acttggtttc cttgctttct tgacatttcc atgactgttt cacatacaaa 660 ctattgggtg aggtttttca gctgttaccg acccacgtcc tgctgtctct gtgtggtcct 720 acaaaaactg tccattccca cccctttgct ttgccatttg caagagtctg gaattgtcag 780 gtctcagctt cgaaaagtcc tggttccact gacaggacac attctttagt gggaattaag 840 acctacaaag tctagtttgt atgtaggtat gaagggaatt ttttaaataa attgaaaagc 900 tgtgaacagc attagaactt tgtctatttc ttaattttaa aatatgctga tatgccttaa 960 actgtagttg tagatccttg tcattttgct gtttgaaaat aaccaatgtg ttttctaaaa 1020 ctgtcgtgta atctactttc attgttaatg cagaattgtc atatatgtaa gctgcatgtt 1080 agacatttgt cttttttaaa ctaaagtaat tgtattgatg tgaagcatat cattttttca 1140 aatatgaaag tgatcactta gcaacatgct tggtaatttg gcatctgtta aggtaggaga 1200 gtggtgaaca gataatctat gcatatatca ctagtgccaa gacataaagc gggggaaaat 1260 atatttttac ccaaacatta aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa caactgtgtt 1320 cggcgcgctt gtggccccgg aagaagagtc ttctcgtaga accatcgtgg tttgggccca 1380 gcggggcccc aggaggtagg gtgccacacg ggccaaaagc gtgtcccagg agacacccgg 1440 gggcactaga acaacttagg gtgtgtgagg aatattttcg ctcaccccat gttacaaaaa 1500 caaccgcgca gagggggcaa acagcaacag ggtttctgtg aaacaacaac ccccaaatgg 1560 agggaagtcc tcgagaagga catacaggga aagcctaata caacagaggg aagatcccaa 1620 ggaaaagcac tatcatataa ataattatcg ccgccggctg tgcggg 1666 169 633 DNA Homo sapien 169 aaaacaacac ggaatgtcta cgactaacta tagggcccct ggtgtatcta gatgcatgct 60 cgagccggcc gccatgatgt gactggatgt cgcggccgag gtacagagta tgtagtgggc 120 atctgttgaa tgaatgcttt tcccagtacg cacgtgtatt catacaatat taatataatt 180 agtcccctgg gcttacagat aaaaatgaaa cgcatcaacg tgcccagctg cagtgagacc 240 caggtgttct tcctccaccc ctagtggtcc cctgggcagg tctttttttt ttggtaacac 300 tcaccaggtc tgttctgtag tcaatcatgt gatggactgt gtcggtgaac tgtgcaggac 360 actgttctca tagtgttcat tagcgacaga gtaaacatgt ttgccatgca agggttattt 420 ggcatctgca tttaagtgat aatgttgaat caatgaaaag gtgttgatta agcagtagtt 480 gtagatatgc taagtttttc aaattactaa tatcaagtgg agatggtttt tactttataa 540 gggtattgct ttggtgatag cataaataat gggtttccct ttttggtaac tgtaacatta 600 attggctggc aactttggta ttcccataga ctg 633 170 563 DNA Homo sapien 170 gggaaggaag acatataggg cggaatgggt cctagatgca tgtcgagcgg cgcagtgtga 60 tggatcggcg ccgggcaggt acaaaaaata ggataaatgc ttgttttttt atttagcaat 120 gtccaaaata atgaattgat ttcccgagta tcctctaaag gtaaccaggg atttttttta 180 tttaattatc ttgaacccac atatttaaat atacgtagta tgctacaaac cattgcagtt 240 aagtaccttt attgatgctt gagttgccca ctttttcttt tttttttttt ggagacagag 300 cctcgctctg tcacccaggc tggagtgcag gggcgtcatc tttgactcac ttgcaacctt 360 ccttccttcc gtggggtgca ggcagattct cctgtgcctt acagcctccg agtttggctg 420 ggatttacag ggcattgttg caagtttccc acattttcag tgagaaattc ctcaattggc 480 ctccgtgagt ggtttggaaa ttgaccccag aattcttgga gtgggtgtat tagctatcta 540 tggctggtgt aacaaattga cct 563 171 682 DNA Homo sapien 171 gaaaaggttg gcagcaggtg cacgtgttat cagcctgatc atctatcacc tgatggtttt 60 agcaatacct aaatccgtga tatcatcaga ggttgcaaaa tgatgagatt caggtttttt 120 ttttacataa ttattggtca gaattattct gcaaatagct tctctttaac agtattcggt 180 taccttgaaa tacaggttgt acaaaaaata ggataaatgc ttgttttttt atttagcaat 240 gtccaaaata atgaattgat ttcccagtat cctctaaagg taaccaggga ttttttttat 300 ttaattatct tgaacccaca tatttaaata tacgtagtat gctacaaacc attgcagtta 360 atacctttat tgatgcttga gttgcccact tttttctttt tttttttttg gagacagagc 420 ctcgctctgt cacccaggct ggagtgcagg ggcgtcatct ttgactcact tgcaaccttc 480 cttccttccg tggggtgcag gcagattctc ctgtgcctta cagcctccga gtttggctgg 540 gatttacagg gcattgttgc aagtttccca cattttcagt gagaaattcc tcaattggcc 600 tccgtgagtg gtttggaaat tgaccccaga attcttggag tgggtgtatt agctatctat 660 ggctggtgta acaaattgac ct 682 172 75 PRT Homo sapien 172 Met Gly Pro Arg Ser Arg Leu Trp Pro Ser Ser Pro Leu Trp Leu Val 1 5 10 15 Gln Pro Leu Cys Thr Pro Gly Val Phe Thr Pro Gly Ala Asp Ser Ser 20 25 30 His Cys Ser Ser Phe Leu Arg Glu Ile Thr Val Val Ile Ala Ala Gly 35 40 45 Ala Asn Arg Leu Gly Leu Val Ser Cys Ala Phe Gly Gln Leu Leu Thr 50 55 60 Arg Ser Ser Leu Lys Gln Trp Gly Gly Pro His 65 70 75 173 38 PRT Homo sapien 173 Met Phe Pro Arg Leu Asp Ser Thr Ser Trp Pro Gln Gly Ile Leu Trp 1 5 10 15 Ala Trp Thr Pro Lys Pro Leu Arg Leu Glu Val Cys Glu Pro Pro Ser 20 25 30 Leu Pro Ser Leu Trp Ser 35 174 52 PRT Homo sapien 174 Met Thr Leu Phe Ile Arg Cys Cys Thr Asn Tyr Gly Asn Leu Cys Gln 1 5 10 15 Tyr Phe Asn Val Cys Trp Ile Ile Thr Asp Ile Phe Ile Ile Leu Met 20 25 30 Ser Thr Asn Leu Phe Ile Leu Ile Ala Arg Val Ser Leu Gly Ser Lys 35 40 45 His His Leu Gly 50 175 37 PRT Homo sapien 175 Met Ala Gly Ser Gly Lys Val Pro Ile Thr Thr Thr Tyr Lys Pro Pro 1 5 10 15 Thr Asn Ser Asn Ala Ile His Leu Pro Thr Pro Ile Ile Arg Lys Ala 20 25 30 Gly Phe Thr Gly Ile 35 176 88 PRT Homo sapien 176 Met Gly Leu Thr Leu Lys Ser Leu Cys Asp Ser Lys Met Asn Cys Gln 1 5 10 15 Ser Asn Val Pro Leu Met Lys Asp Pro Ile Thr Leu Gln His Val Cys 20 25 30 Ile Gln Arg Thr Tyr Leu Arg Leu Ser Phe Gly His Gly Gly Arg Leu 35 40 45 Leu Leu Lys Thr Tyr Gln Ser Pro Leu Trp Arg Ser Ala Asp Arg Pro 50 55 60 His Asp Leu Gly Asn Gly Leu Leu Val Ile Trp Asp Cys Leu Gly Leu 65 70 75 80 Cys Asn Gly Thr Trp Gly Gln Asn 85 177 61 PRT Homo sapien 177 Met Asp His Lys Ser Ala Asn His Ser Ser Ala Leu Leu Lys Met Leu 1 5 10 15 Leu Ala Gly Gly Met Ser Leu Pro Glu Val Pro Glu Gly Leu Thr Pro 20 25 30 Thr Pro Ser Ser Gln Thr His Leu Ser Lys Gly Lys Gly Arg Asn Leu 35 40 45 Glu Lys Ser Tyr Phe His Asn His Ser Leu Arg Glu Pro 50 55 60 178 198 PRT Homo sapien 178 Met Thr Pro Ile His Leu Ile Cys Ser Pro Ser His Glu Leu Gln Asp 1 5 10 15 Thr Thr His Pro Gln Pro Gln Arg Glu Cys Gln Arg Phe Ser Thr His 20 25 30 Gly Ala Gln Thr Thr Gln Cys Ala Thr His His His Pro Tyr Ile Ser 35 40 45 Gly Ala Ala Thr Arg Thr Tyr Leu Arg His Val Ala Pro Asp Tyr Ser 50 55 60 Ala Pro Leu Met Ala Pro Pro Thr Asn Thr Arg Leu Ala Pro Ala Ser 65 70 75 80 Leu Gln Pro Thr His Leu Arg Pro Pro Leu Ala Arg His Pro Leu Thr 85 90 95 Ala Asp Cys Arg Thr His Gln Leu Thr Asp Thr Arg Pro Leu His Pro 100 105 110 Arg Pro Ile Thr Ser Arg Thr Pro Gln Pro Leu Pro Ser His Thr His 115 120 125 Gly Leu His His Thr Arg Pro Pro His Thr Ala Thr Gly Cys Pro Tyr 130 135 140 Leu Ser Thr Ser Arg Pro Leu Pro Pro Leu His Thr Arg Ser Ile His 145 150 155 160 Pro Asp Asn Pro His Cys Thr Thr Pro His His Ser Pro Ser Lys Pro 165 170 175 Ser Thr Thr Thr His Gln Gln Ser Pro Ala Pro Thr Pro Asn Lys Pro 180 185 190 His Pro Arg Arg Ala Ser 195 179 20 PRT Homo sapien 179 Met Ile Gly Ile Thr Trp Cys Phe Glu Leu Ile His Pro Thr Leu Glu 1 5 10 15 Leu Thr Ala Thr 20 180 107 PRT Homo sapien 180 Met Gly Ala Ser Gly Pro Glu Arg Glu Asp Arg Asn Ser Glu Asn Gly 1 5 10 15 Val Glu Lys Lys Asn Val Lys Glu Leu His Glu Glu His Met Ala Glu 20 25 30 Lys Lys Glu Leu Gln Glu Glu Asn Gln Arg Leu Gln Gly Leu Pro Val 35 40 45 Ser Gly Ser Glu Glu Gly Arg Leu Pro Val Pro Ser Ala Arg Ser Ser 50 55 60 Thr Leu Arg Ala Ser Cys Arg Asn Glu Leu Gly Ser Leu Leu Pro Gly 65 70 75 80 Gly Glu Thr Ser Leu Gly Leu Lys Glu Gly His Arg Thr Lys Gly Ala 85 90 95 Arg Gly Gly His Arg Glu Asp Pro Gln Glu Lys 100 105 181 27 PRT Homo sapien 181 Met Ser Thr His Ser Val His Ser Thr Gly Leu Pro Phe Tyr Lys Leu 1 5 10 15 Ser Leu Thr Ser Leu Ser Ser Met Thr Leu Val 20 25 182 40 PRT Homo sapien 182 Cys Phe Glu Lys Met Leu Asn Arg Leu Gly Ala Val Ala His Val Cys 1 5 10 15 Asn Pro Ser Thr Leu Gly Gly Arg Gly Gly Trp Ile Met Arg Ser Gly 20 25 30 Val Arg Asp Gln Pro Gly Gln His 35 40 183 26 PRT Homo sapien 183 Met Arg Lys Gln Ala Phe Asp Leu Leu Glu Ser Thr Ala Gln Lys Ser 1 5 10 15 Leu Val Pro Ile Phe Glu Phe Pro Lys Gln 20 25 184 39 PRT Homo sapien 184 Met Lys Glu Glu Gly Arg Leu Leu Thr Val Ala Glu Gly Arg Gln Gly 1 5 10 15 Pro Ser Cys Ser Ser His Ile Asn Ser Lys Lys Pro Ser Gln Gln Asn 20 25 30 Lys Ser Ile Phe Asn Ser Ser 35 185 76 PRT Homo sapien 185 Met Val Glu Pro Ala Leu Ser Gly Cys Gln Gln Arg Lys Gly Gly Tyr 1 5 10 15 Ser Ser Glu Arg Gln Ser Gln Pro Thr Gln Gly Gly Gln Gly Val Arg 20 25 30 Pro Gln Thr Tyr Ser Pro Ala Asp Leu Thr Val Arg Pro Ser Cys Ser 35 40 45 Gly Thr Gly Asn Ala Gln Ala Glu Ile Ala Leu Leu His Thr Tyr Asn 50 55 60 Thr Thr Leu Glu Asn Asn Leu Glu Trp Phe Thr Leu 65 70 75 186 35 PRT Homo sapien 186 Met Arg Gln Pro Cys Leu Ala Ile Pro Glu Ala Ser Ala Ser Leu Ile 1 5 10 15 Cys Arg Cys His Arg His Phe Thr Tyr Ser His Leu Met Ala Arg Phe 20 25 30 Leu Leu Leu 35 187 76 PRT Homo sapien 187 Met Phe Phe Ala Leu Met Gly Ile Cys Pro Gly Thr Leu Pro Pro Gly 1 5 10 15 Pro Pro Leu Pro Arg Trp Pro Pro Pro Val Phe Cys Phe Phe Phe Phe 20 25 30 Phe Phe Gly Phe Phe Phe Cys Cys Phe Thr Val Lys Leu Phe Ile Glu 35 40 45 Gln Ile Glu Asp Asn Asp Ile Cys Phe Tyr Tyr Arg Ser Leu Pro Ser 50 55 60 Ser Tyr Ile Ile Asp Thr Tyr Tyr Glu Thr Cys Ile 65 70 75 188 173 PRT Homo sapien 188 Met Ile Gly Cys Ser Leu Leu Val Ala Cys Leu Cys Cys Leu Val Gln 1 5 10 15 Ser Phe Arg Ala Met Phe Ser Cys Phe Ser Gly Leu Ser Leu Cys Leu 20 25 30 Met Leu Pro Leu Trp Cys Val Cys Pro Thr Val Cys Ala Phe Phe Cys 35 40 45 Gly Tyr Leu Leu Phe Phe Ser Leu Arg His Ala Ala Cys Gly Cys Leu 50 55 60 Leu Val Cys Leu Ser Cys Leu Ala Leu Pro Ser Gly Pro Ile Leu Ser 65 70 75 80 Phe Ser Phe Cys Leu Arg Val Val Ser Ser Val Arg Val Ala Cys Ala 85 90 95 Arg Ser Ala Ala Val Leu Leu Leu Arg Gly Val Pro Pro Pro Ser Leu 100 105 110 Arg Thr Leu Ser Leu Ile Ala Ser Thr Ala Thr Arg Leu Ser Phe Val 115 120 125 Phe Leu Phe Ser Leu Pro Arg Gly Leu Leu Cys Val Gly Gly Ser Gly 130 135 140 Ser Val Leu Gly Ser Leu Val Arg Arg Ala Gln Ser Val Gly Leu Arg 145 150 155 160 Asp Phe Val Ser Val Leu Gln Val Val Leu Thr Cys Leu 165 170 189 29 PRT Homo sapien 189 Met Val Leu Tyr Ser Glu Gly His Gln His Gly Pro His Leu Leu Asn 1 5 10 15 Met Glu Asn Gln Asn Leu Asn Glu Leu Pro Leu Lys Gly 20 25 190 122 PRT Homo sapien 190 Phe Phe Ala Asp Glu Val Ser Arg Leu Ser Pro Gly Leu Glu Cys Ser 1 5 10 15 Gly Val Ile Ser Ala His Cys Asn Phe His Leu Leu Gly Ser Ser Ser 20 25 30 Ser Pro Ala Ser Ala Ser Gln Val Ala Glu Ile Thr Gly Ala Cys His 35 40 45 Pro Thr Trp Leu Ile Phe Val Ile Leu Val Glu Thr Gly Phe His His 50 55 60 Val Gly Gln Ala Asp Ala Leu Leu Thr Ser Gly Asp Pro Pro Phe Ser 65 70 75 80 Ala Pro Lys Val Leu Gly Ile Thr Gly Val Ser His Arg Ala Arg Pro 85 90 95 Ala Asn Thr Phe Ala Leu Thr Thr Leu Gly Leu Leu Tyr Lys Ile Val 100 105 110 Met Ile Ala Met Glu Val Leu Pro Val Pro 115 120 191 11 PRT Homo sapien 191 Met Trp Arg Ala Lys Gln Tyr Asp Leu Gln Thr 1 5 10 192 28 PRT Homo sapien 192 Met Met Phe Ser Leu Ser Gln Lys Gly Ser Ala Ala Val Gln Ser Pro 1 5 10 15 Ser Thr Leu Ser Thr Pro Thr Phe Ser Ile Ser Tyr 20 25 193 48 PRT Homo sapien 193 Met Asp Ser Gly Ala Arg Ala Gly Lys Pro Leu Leu Asp Pro Val Cys 1 5 10 15 Leu Pro Ala Trp Ser Leu Cys Leu Gln Pro Cys Leu Tyr Ser Ser Leu 20 25 30 Pro Pro His Gln Pro Pro Leu Ala Ser Pro Tyr Arg Leu Ser Lys Lys 35 40 45 194 1138 PRT Homo sapien 194 Met Gly Asp Phe Ala Ala Pro Ala Ala Ala Ala Asn Gly Ser Ser Ile 1 5 10 15 Cys Ile Asn Ser Ser Leu Asn Ser Ser Leu Gly Gly Ala Gly Ile Gly 20 25 30 Val Asn Asn Thr Pro Asn Ser Thr Pro Ala Ala Pro Ser Ser Asn His 35 40 45 Pro Ala Ala Gly Gly Cys Gly Gly Ser Gly Gly Pro Gly Gly Gly Ser 50 55 60 Ala Ala Val Pro Lys His Ser Thr Val Val Glu Arg Leu Arg Gln Arg 65 70 75 80 Ile Glu Gly Cys Arg Arg His His Val Asn Cys Glu Asn Arg Tyr Gln 85 90 95 Gln Ala Gln Val Glu Gln Leu Glu Leu Glu Arg Arg Asp Thr Val Ser 100 105 110 Leu Tyr Gln Arg Thr Leu Glu Gln Arg Ala Lys Lys Ser Gly Ala Gly 115 120 125 Thr Gly Lys Gln Gln His Pro Ser Lys Pro Gln Gln Asp Ala Glu Ala 130 135 140 Ala Ser Ala Glu Gln Arg Asn His Thr Leu Ile Met Leu Gln Glu Thr 145 150 155 160 Val Lys Arg Lys Leu Glu Gly Ala Arg Ser Pro Leu Asn Gly Asp Gln 165 170 175 Gln Asn Gly Ala Cys Asp Gly Asn Phe Ser Pro Thr Ser Lys Arg Ile 180 185 190 Arg Lys Asp Ile Ser Ala Gly Met Glu Ala Ile Asn Asn Leu Pro Ser 195 200 205 Asn Met Pro Leu Pro Ser Ala Ser Pro Leu His Gln Leu Asp Leu Lys 210 215 220 Pro Ser Leu Pro Leu Gln Asn Ser Gly Thr His Thr Pro Gly Leu Leu 225 230 235 240 Glu Asp Leu Ser Lys Asn Gly Arg Leu Pro Glu Ile Lys Leu Pro Val 245 250 255 Asn Gly Cys Ser Asp Leu Glu Asp Ser Phe Thr Ile Leu Gln Ser Lys 260 265 270 Asp Leu Lys Gln Glu Pro Leu Asp Asp Pro Thr Cys Ile Asp Thr Ser 275 280 285 Glu Thr Ser Leu Ser Asn Gln Asn Lys Leu Phe Ser Asp Ile Asn Leu 290 295 300 Asn Asp Gln Glu Trp Gln Glu Leu Ile Asp Glu Leu Ala Asn Thr Val 305 310 315 320 Pro Glu Asp Asp Ile Gln Asp Leu Phe Asn Glu Asp Phe Glu Glu Lys 325 330 335 Lys Glu Pro Glu Phe Ser Gln Pro Ala Thr Glu Thr Pro Leu Ser Gln 340 345 350 Glu Ser Ala Ser Val Lys Ser Asp Pro Ser His Ser Pro Phe Ala His 355 360 365 Val Ser Met Gly Ser Pro Gln Ala Arg Pro Ser Ser Ser Gly Pro Pro 370 375 380 Phe Ser Thr Val Ser Thr Ala Thr Ser Leu Pro Ser Val Ala Ser Thr 385 390 395 400 Pro Ala Ala Pro Asn Pro Ala Ser Ser Pro Ala Asn Cys Ala Val Gln 405 410 415 Ser Pro Gln Thr Pro Asn Gln Ala His Thr Pro Gly Gln Ala Pro Pro 420 425 430 Arg Pro Gly Asn Gly Tyr Leu Leu Asn Pro Ala Ala Val Thr Val Ala 435 440 445 Gly Ser Ala Ser Gly Pro Val Ala Val Pro Ser Ser Asp Met Ser Pro 450 455 460 Ala Glu Gln Leu Lys Gln Met Ala Ala Gln Gln Gln Gln Arg Ala Lys 465 470 475 480 Leu Met Gln Gln Lys Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln 485 490 495 Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln His Ser 500 505 510 Asn Gln Thr Ser Asn Trp Ser Pro Leu Gly Pro Pro Ser Ser Pro Tyr 515 520 525 Gly Ala Ala Phe Thr Ala Glu Lys Pro Asn Ser Pro Met Met Tyr Pro 530 535 540 Gln Ala Phe Asn Asn Gln Asn Pro Ile Val Pro Pro Met Ala Asn Asn 545 550 555 560 Leu Gln Lys Thr Thr Met Asn Asn Tyr Leu Pro Gln Asn His Met Asn 565 570 575 Met Ile Asn Gln Gln Pro Asn Asn Leu Gly Thr Asn Ser Leu Asn Lys 580 585 590 Gln His Asn Ile Leu Thr Tyr Gly Asn Thr Lys Pro Leu Thr His Phe 595 600 605 Asn Ala Asp Leu Ser Gln Arg Met Thr Pro Pro Val Ala Asn Pro Asn 610 615 620 Lys Asn Pro Leu Met Pro Tyr Ile Gln Gln Gln Gln Gln Gln Gln Gln 625 630 635 640 Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Pro Pro Pro Pro Gln Leu 645 650 655 Gln Ala Pro Arg Ala His Leu Ser Glu Asp Gln Lys Arg Leu Leu Leu 660 665 670 Met Lys Gln Lys Gly Val Met Asn Gln Pro Met Ala Tyr Ala Ala Leu 675 680 685 Pro Ser His Gly Gln Glu Gln His Pro Val Gly Leu Pro Arg Thr Thr 690 695 700 Gly Pro Met Gln Ser Ser Val Pro Pro Gly Ser Gly Gly Met Val Ser 705 710 715 720 Gly Ala Ser Pro Ala Gly Pro Gly Phe Leu Gly Ser Gln Pro Gln Ala 725 730 735 Ala Ile Met Lys Gln Met Leu Ile Asp Gln Arg Ala Gln Leu Ile Glu 740 745 750 Gln Gln Lys Gln Gln Phe Leu Arg Glu Gln Arg Gln Gln Gln Gln Gln 755 760 765 Gln Gln Gln Gln Ile Leu Ala Glu Gln Gln Leu Gln Gln Ser His Leu 770 775 780 Pro Arg Gln His Leu Gln Pro Gln Arg Asn Pro Tyr Pro Val Gln Gln 785 790 795 800 Val Asn Gln Phe Gln Gly Ser Pro Gln Asp Ile Ala Ala Val Arg Ser 805 810 815 Gln Ala Ala Leu Gln Ser Met Arg Thr Ser Arg Leu Met Ala Gln Asn 820 825 830 Ala Gly Met Met Gly Ile Gly Pro Ser Gln Asn Pro Gly Thr Met Ala 835 840 845 Thr Ala Ala Ala Gln Ser Glu Met Gly Leu Ala Pro Tyr Ser Thr Thr 850 855 860 Pro Thr Ser Gln Pro Gly Met Tyr Asn Met Ser Thr Gly Met Thr Gln 865 870 875 880 Met Leu Gln His Pro Asn Gln Ser Gly Met Ser Ile Thr His Asn Gln 885 890 895 Ala Gln Gly Pro Arg Gln Pro Ala Ser Gly Gln Gly Val Gly Met Val 900 905 910 Ser Gly Phe Gly Gln Ser Met Leu Val Asn Ser Ala Ile Thr Gln Gln 915 920 925 His Pro Gln Met Lys Gly Pro Val Gly Gln Ala Leu Pro Arg Pro Gln 930 935 940 Ala Pro Pro Arg Leu Gln Ser Leu Met Gly Thr Val Gln Gln Gly Ala 945 950 955 960 Gln Ser Trp Gln Gln Arg Ser Leu Gln Gly Met Pro Gly Arg Thr Ser 965 970 975 Gly Glu Leu Gly Pro Phe Asn Asn Gly Ala Ser Tyr Pro Leu Gln Ala 980 985 990 Gly Gln Pro Arg Leu Thr Lys Gln His Phe Pro Gln Gly Leu Ser Gln 995 1000 1005 Ser Val Val Asp Ala Asn Thr Gly Thr Val Arg Thr Leu Asn Pro 1010 1015 1020 Ala Ala Met Gly Arg Gln Met Met Pro Ser Leu Pro Gly Gln Gln 1025 1030 1035 Gly Thr Ser Gln Ala Arg Pro Met Val Met Ser Gly Leu Ser Gln 1040 1045 1050 Gly Val Pro Gly Met Pro Ala Phe Ser Gln Pro Pro Ala Gln Gln 1055 1060 1065 Gln Ile Pro Ser Gly Ser Phe Ala Pro Ser Ser Gln Ser Gln Ala 1070 1075 1080 Tyr Glu Arg Asn Ala Pro Gln Asp Val Ser Tyr Asn Tyr Ser Gly 1085 1090 1095 Asp Gly Ala Gly Gly Ser Phe Pro Gly Leu Pro Asp Gly Ala Asp 1100 1105 1110 Leu Val Asp Ser Ile Ile Lys Gly Gly Pro Gly Asp Glu Trp Met 1115 1120 1125 Gln Glu Leu Asp Glu Leu Phe Gly Asn Pro 1130 1135 195 30 PRT Homo sapien 195 Met Gln Leu Pro Leu Ser His Lys Arg Lys Lys Gln Tyr Ser Phe Tyr 1 5 10 15 Val Phe Asp Thr Asn Ile Lys His Asn Ser Val Leu Val His 20 25 30 196 46 PRT Homo sapien 196 Met Lys Ile Tyr Phe Lys Ile Leu Leu Met Phe Leu Lys Lys Tyr Phe 1 5 10 15 Leu Arg Phe His Leu Met Lys Thr Met Lys Tyr Ser Val Phe Tyr Ser 20 25 30 Thr Thr Arg Gln Met Trp Ser Ile Pro Phe Val Phe Phe Phe 35 40 45 197 18 PRT Homo sapien 197 Met Leu Glu Ala Gly Ile Ser Phe Lys Val Arg Leu Gln Lys Trp Lys 1 5 10 15 Gln Ile 198 132 PRT Homo sapien 198 Met Phe Tyr Ser Ile Leu Ala Met Leu Arg Asp Arg Gly Ala Leu Gln 1 5 10 15 Asp Leu Met Asn Met Leu Glu Leu Asp Ser Ser Gly His Leu Asp Gly 20 25 30 Pro Gly Gly Ala Ile Leu Lys Lys Leu Gln Gln Asp Ser Asn His Ala 35 40 45 Trp Phe Asn Pro Lys Asp Pro Ile Leu Tyr Leu Leu Glu Ala Ile Met 50 55 60 Val Leu Ser Asp Phe Gln His Asp Leu Leu Ala Cys Ser Met Glu Lys 65 70 75 80 Arg Ile Leu Leu Gln Gln Gln Glu Leu Val Arg Ser Ile Leu Glu Pro 85 90 95 Asn Phe Arg Tyr Pro Trp Ser Ile Pro Phe Thr Leu Lys Pro Glu Leu 100 105 110 Leu Ala Pro Leu Gln Ser Glu Gly Leu Ala Ser Pro Met Ala Ala Gly 115 120 125 Gly Val Trp Pro 130 199 226 PRT Homo sapien 199 Pro Pro Lys His Leu Lys Ser Lys Phe Gly Gly Met Arg Lys Ala Asp 1 5 10 15 Asp Asp Leu Ile Leu Leu Leu Gly Arg Ile Glu Glu Pro Phe Trp Gln 20 25 30 Asn Phe Lys His Leu Gln Glu Glu Val Phe Gln Lys Ile Lys Thr Leu 35 40 45 Ala Gln Leu Ser Lys Asp Val Gln Asp Val Met Phe Tyr Ser Ile Leu 50 55 60 Ala Met Leu Arg Asp Arg Gly Ala Leu Gln Asp Leu Met Asn Met Leu 65 70 75 80 Glu Leu Asp Ser Ser Gly His Leu Asp Gly Pro Gly Gly Ala Ile Leu 85 90 95 Lys Lys Leu Gln Gln Asp Ser Asn His Ala Trp Phe Asn Pro Lys Asp 100 105 110 Pro Ile Leu Tyr Leu Leu Glu Ala Ile Met Val Leu Ser Asp Phe Gln 115 120 125 His Asp Leu Leu Ala Cys Ser Met Glu Lys Arg Ile Leu Leu Gln Gln 130 135 140 Gln Glu Leu Val Arg Ser Ile Leu Glu Pro Asn Phe Arg Tyr Pro Trp 145 150 155 160 Ser Ile Pro Phe Thr Leu Lys Pro Glu Leu Leu Ala Pro Leu Gln Ser 165 170 175 Glu Gly Leu Ala Ile Thr Tyr Gly Leu Leu Glu Glu Cys Gly Leu Arg 180 185 190 Thr Glu Leu Asp Asn Pro Arg Ser Thr Trp Asp Val Glu Ala Lys Met 195 200 205 Pro Leu Ser Ala Leu Tyr Gly Thr Leu Ser Leu Leu Gln Gln Leu Ala 210 215 220 Glu Ala 225 200 37 PRT Homo sapien 200 Met Ala Lys His Lys Gly Gly Tyr Gly Lys Tyr Trp Val Thr Leu Ile 1 5 10 15 Ile Gly Leu Asn Ala Thr Asn Asn Ile Ile Ile Val Leu Thr Tyr Phe 20 25 30 Phe Arg Leu Leu Ser 35 201 28 PRT Homo sapien 201 Met Val His Lys Ser Tyr Phe Thr Thr Leu Ser Leu Val Ile Leu Gly 1 5 10 15 Val Trp Pro Cys Lys Ala Ser Ser Gln Arg Phe Cys 20 25 202 77 PRT Homo sapien 202 Met Gly Ser Val Cys Val Cys Phe His Arg Ser Thr Thr Ser Glu Val 1 5 10 15 Ser Leu His Leu Cys Ile Phe Thr Ser Gln Gly Gln Gly Pro Gly Asn 20 25 30 Leu Arg Gly Ser His Ser Phe Ser Leu Pro Gln Thr Met Pro Leu Pro 35 40 45 Pro Ile Ser Leu Gly Gln Glu Ser Gly Phe Cys Phe Pro Tyr Phe Phe 50 55 60 Phe Pro Arg His Trp Glu Ala Ser Gly Glu Gln His Gln 65 70 75 203 70 PRT Homo sapien 203 Met Gly Pro Pro Leu Pro Leu Gly Gly Trp Ser Ser Asp Leu Leu Ala 1 5 10 15 Gln Lys Val Leu Phe Phe His Leu Leu Cys Leu Asn Glu Ser Ser Trp 20 25 30 Thr Tyr Thr Pro Leu Ser Asp Glu Arg Ala Arg Leu Arg Arg Cys Ala 35 40 45 Gly His Leu Leu Arg Ile His Val Gly Ser Ala Ala Pro Gly Gly Gly 50 55 60 Ser Thr Ser Ala Ala Thr 65 70 204 37 PRT Homo sapien 204 Met Ser Lys Lys Lys Asp Gln Asp Leu Cys Leu Lys Ile Glu Met His 1 5 10 15 Thr Ala Ala Ala Gln Lys Leu Arg Pro Ala Ser Lys Leu His Glu Ala 20 25 30 Leu Val Lys Thr Asp 35 205 87 PRT Homo sapien 205 Met Pro Ser Val Ala Gln Gly Pro Val Pro Trp His Leu Gly Ser Arg 1 5 10 15 Ser Ala Val Ala Val Phe Glu Phe Leu Val Met Phe Glu Gln Arg Pro 20 25 30 Tyr Val Cys Ile Leu His Trp Ala Pro Gln Ile Thr Trp Pro Ile Leu 35 40 45 Arg Arg Gly Val Ser His Leu Gln Ser Pro Lys Ser Pro Leu Glu Val 50 55 60 Phe Leu Asn Glu Arg Thr Glu Ala Phe Leu Lys Ser Ser Val Gly Glu 65 70 75 80 Thr Val His His His Thr Gln 85 206 46 PRT Homo sapien 206 Met Ser Pro Gly Thr Ala Met Ala Leu Gly Ala Pro Thr Leu Phe Phe 1 5 10 15 Phe Phe Phe Phe Phe Phe Phe Tyr Asn Gln Pro Ile Arg Asp Leu Ser 20 25 30 Ile Asn Lys Pro Leu Phe Ile Ile Arg Asn Trp Leu Thr Gln 35 40 45 207 91 PRT Homo sapien 207 Met Ser Ser Pro Gln Ser Ile Glu His Asn His Asp Ser His Glu Leu 1 5 10 15 Pro Thr Pro Pro Ala Ala Ser Ala Gln Arg Glu Ser Pro Leu Gln Val 20 25 30 Cys Leu Ile Ala Glu Pro Ile Phe Phe Leu Pro Gly Gln Gln Leu Leu 35 40 45 Ser Ser Met Ser Arg His Trp Cys Ser Leu Gly Trp Ala Pro Val Thr 50 55 60 Pro Met Glu Ile Leu Asp Gly Cys Tyr Arg Thr Gly Leu Asp Val Arg 65 70 75 80 Gly Leu Gly Asn Gly Ala Gln Glu Ser Ser Ser 85 90 208 87 PRT Homo sapien 208 Met Cys Val Arg Asn Ser Met Phe Lys Lys Glu Ile Ile Gln Arg Val 1 5 10 15 Thr Asn His Gly Ser Val Gly His Trp Thr Lys Leu Gly Phe Trp Thr 20 25 30 Phe Leu Pro Asn Ile Asn Phe Ala Leu Ala Ser Val Tyr Thr His Thr 35 40 45 His Thr Thr Thr Asn Thr Thr Gln Thr Thr Phe Trp Ala Asn Thr Thr 50 55 60 Arg Arg Gln Arg Arg Leu Pro Gly Leu Lys Leu Gly Ser Leu Pro Ala 65 70 75 80 Pro Gln Phe Ser Gln Gln Leu 85 209 55 PRT Homo sapien 209 Met Thr Cys Phe Arg Glu Cys Leu Leu Val Tyr Leu Tyr Ser Ile Cys 1 5 10 15 Leu Leu Asn Ser Leu His Lys Leu Glu Leu Leu Ser Arg Arg Leu Arg 20 25 30 Glu Cys Lys Tyr Val Thr His Lys Met His Trp Ser Met Val Asn Lys 35 40 45 Thr Asn His Phe Gly Leu Val 50 55 210 58 PRT Homo sapien 210 Met Val Ile Phe Tyr Ser Ser Pro Ser Gln Asp Ser Ala Leu Ile Tyr 1 5 10 15 Tyr Ile Pro Phe Ile Leu Leu Tyr Arg Leu Leu Ser Glu Thr His Val 20 25 30 Gln Ile Arg Asp Lys Ile Leu Lys His Ile Thr Pro Ser Leu Val Phe 35 40 45 Ser Ile Gln Ile Leu Arg Asn Ser Cys Tyr 50 55 211 37 PRT Homo sapien 211 Met Asn Leu Tyr Leu Lys Met Lys Thr Ile Pro Lys Lys Thr Cys Met 1 5 10 15 Ser Lys Thr Glu Leu Phe Leu Pro Phe Thr Pro Lys Tyr Leu Lys Leu 20 25 30 Asn Leu Ser His Phe 35 212 99 PRT Homo sapien 212 Phe Phe Phe Phe Leu Arg Trp Ser Leu Ala Leu Ser Pro Arg Leu Glu 1 5 10 15 Cys Ser Gly Val Ile Ser Thr His Cys Asn Leu Cys Phe Pro Gly Ser 20 25 30 Ser Asp Ser Arg Ala Ser Pro Thr Phe Gln Val Ala Trp Ile Thr Gly 35 40 45 Val Arg His His Ser Trp Leu Ile Phe Val Leu Leu Val Glu Thr Gly 50 55 60 Phe His His Val Val Gln Ala Val Glu Leu Leu Thr Ser Arg Asp Pro 65 70 75 80 Pro Ala Ser Ala Ser Gln Ser Ala Ala Ile Ile Gly Val Asn His Cys 85 90 95 Ala Arg Pro 213 43 PRT Homo sapien 213 Met Gln Glu Phe Thr Trp Leu Phe Glu Lys Glu Asn Phe Lys Val Ser 1 5 10 15 Gly Trp Thr Glu Ser His Glu Ala Arg Ser Leu Leu Thr Ala Arg Ser 20 25 30 Leu Glu Lys Gln Val Ser Gly Ser Phe Thr Ser 35 40 214 61 PRT Homo sapien 214 Met Ala Val Asp Phe Tyr Asn Phe Val Thr Lys Leu Val Val Thr Thr 1 5 10 15 Gly Tyr Leu Arg Ile Ser Phe Leu Ala Tyr Lys Phe Phe Ser Phe Pro 20 25 30 Phe Leu Asp Ser Leu Ser Leu Cys Cys Pro Gly Leu Glu Cys Ser Gly 35 40 45 Val Ile Pro Ala His Tyr Asn Leu Tyr Leu Pro Gly Arg 50 55 60 215 127 PRT Homo sapien 215 Ser Gln Asn Ile Phe Phe Gly Val Ala Ile Phe Phe Phe Ser Phe Phe 1 5 10 15 Arg Gln Ser Leu Ser Leu Val Ala Gln Ala Arg Val Gln Trp Arg Asp 20 25 30 Pro Gly Ser Leu Gln Pro Leu Pro Pro Gly Phe Lys Arg Phe Leu Gly 35 40 45 Leu Ser Leu Pro Ser Ser Ala Gly Tyr Arg Arg Ala Pro Pro Pro Cys 50 55 60 Pro Ala Leu Leu Tyr Phe Ala Val Glu Thr Gly Phe His His Val Gly 65 70 75 80 Gln Ala Gly Leu Glu Leu Leu Thr Ser Gly Asn Pro Ala Ala Ser Ala 85 90 95 Ser Gln Ser Ala Gly Ile Thr Gly Thr Ser His Cys Thr Gln Pro Tyr 100 105 110 Tyr His Lys Ser Ser Ala Cys Trp Tyr Leu Ile Arg Phe Tyr Leu 115 120 125 216 13 PRT Homo sapien 216 Met Glu Cys Ser Ser Leu Ala Glu Phe Lys Pro Val Phe 1 5 10 217 100 PRT Homo sapien 217 Pro Gln Gln Thr Leu Lys Arg Ile Gln Gln Val Leu Ile Lys Cys Cys 1 5 10 15 Leu Ala Phe Tyr Leu Phe Leu Phe Phe Phe Phe Leu Arg Trp Ser Leu 20 25 30 Ala Leu Leu Pro Ser Leu Lys Cys Ser Gly Val Ile Ser Ala His Cys 35 40 45 Asn Leu Arg Leu Pro Gly Leu Gly Asp Ser Leu Ala Ser Ala Ser Arg 50 55 60 Val Ala Gly Met Thr Thr Gly Thr Cys His His Ala Gln Leu Ile Phe 65 70 75 80 Val Phe Leu Val Glu Thr Gly Phe Cys Val Ser Gln Asp Gly Leu Asp 85 90 95 Leu Leu Ile Ser 100 218 46 PRT Homo sapien 218 Met Glu Gly Gly Glu Met Ser Thr Gln Val Glu Asn Arg Ser Glu Gly 1 5 10 15 Thr Ile Pro Ile Gln Thr Thr Cys Lys Ser His Asn Lys Ala Pro His 20 25 30 Cys Thr Glu Leu Arg His Lys Gln Arg Phe Pro Thr Asp Gly 35 40 45 219 72 PRT Homo sapien 219 Ile Ser Phe Ile Phe Phe Ser Glu Ala Cys Gln Val Glu Val Arg Leu 1 5 10 15 Leu Leu Ala Tyr Asn Ser Ser Ala Arg Ile Pro Lys Cys Pro Trp Met 20 25 30 Glu Gly Gly Glu Met Ser Pro Gln Val Glu Thr Ser Ile Glu Gly Thr 35 40 45 Ile Pro Phe Ser Lys Pro Val Lys Val Tyr Ile Met Pro Lys Pro Ala 50 55 60 Arg Arg Pro Lys Pro Ala Arg Arg 65 70 220 41 PRT Homo sapien 220 Met Glu Cys Lys Val Ile Lys Cys Ser Cys Phe His Leu Glu Gly Cys 1 5 10 15 Gly Pro Glu Gly Lys Arg Ser Pro Lys Tyr Pro Pro Pro Trp Cys Ser 20 25 30 Ser Leu Cys Leu Val Pro Ala Arg Ala 35 40 221 30 PRT Homo sapien 221 Met Asn Ser Phe Gly Tyr Met Thr Pro Ser Lys Phe Phe Lys Lys Glu 1 5 10 15 Ile Thr Phe Lys Thr Thr Tyr Ile Phe Cys Phe Cys Leu Arg 20 25 30 222 22 PRT Homo sapien 222 Met Leu Gln Ile Gly His Leu Leu Ser Met His Ser Leu Asp Lys Asn 1 5 10 15 Ile Gly Gln Val Gly Met 20 223 18 PRT Homo sapien 223 Met Ser Asp Arg Val Val Ala Leu Leu Glu Val Phe Phe Pro Phe Gln 1 5 10 15 Arg Glu 224 133 PRT Homo sapien 224 Met Gly Asn Ser Ile Asp Thr Val Arg Tyr Gly Lys Glu Ser Asp Leu 1 5 10 15 Gly Asp Val Ser Glu Glu His Gly Glu Trp Asn Lys Glu Ser Ser Asn 20 25 30 Asn Glu Gln Asp Asn Ser Leu Leu Glu Gln Tyr Leu Thr Ser Val Gln 35 40 45 Gln Leu Glu Asp Ala Asp Glu Arg Thr Asn Phe Asp Thr Glu Thr Arg 50 55 60 Asp Ser Lys Leu His Ile Ala Cys Phe Pro Val Gln Leu Asp Thr Leu 65 70 75 80 Ser Asp Gly Ala Ser Val Asp Glu Ser His Gly Ile Ser Pro Pro Leu 85 90 95 Gln Gly Glu Ile Ser Gln Thr Gln Glu Asn Ser Lys Leu Asn Ala Glu 100 105 110 Val Gln Gly Gln Gln Pro Glu Cys Asp Ser Thr Phe Gln Leu Leu His 115 120 125 Val Gly Val Thr Val 130 225 50 PRT Homo sapien 225 Met Arg Asn Ser Ser Pro Ile Leu Thr Pro Ala Leu Phe Ser Phe His 1 5 10 15 Met Tyr Ile Gly Pro Leu Ile Arg Ile Phe Lys Lys Phe Pro Arg Pro 20 25 30 Pro Asn Leu Thr Ile Asp Asp Pro Leu Ser Leu Phe Arg Arg Asn Tyr 35 40 45 Ile Gly 50 226 43 PRT Homo sapien 226 Met His Ser Phe Phe Leu Ser Met Leu Cys Pro Glu Ala Leu Arg Val 1 5 10 15 Leu Leu Lys Gln Ala Ala Gly Leu Leu Arg Glu Ile Lys Gly Phe Ile 20 25 30 Ser Thr Thr Arg Cys Gln Asn Leu His Phe Glu 35 40 227 99 PRT Homo sapien 227 Met Leu Glu Arg Arg Ser Val Met Asp Arg Arg Arg Ala Gly Asn Ser 1 5 10 15 Pro Pro Arg Ile Glu Lys Cys Leu Leu Gly Arg Glu Glu Gly Glu Ala 20 25 30 Gly Ala Gly Pro Ser Pro Gly Ser Leu Leu Gly Pro Gln Lys Ala Leu 35 40 45 Asn Gln Ala Pro Ser Leu Gln Gly Lys Pro Arg Pro Gln Pro Asp Asn 50 55 60 Leu Glu Gly Arg Lys Ser Gln Thr Leu Gly Leu Phe Phe Gly Gly Ile 65 70 75 80 Ile Gly Phe Phe Phe Phe Met Phe Leu Leu Glu Phe Cys Leu Leu Ala 85 90 95 Asn Ser Val 228 44 PRT Homo sapien 228 Met Lys Ser Ile Gln Leu Lys Phe Ser Tyr Ile Ile Glu Pro Gln Leu 1 5 10 15 Asn Gly Met Asn Gly Ile Gly Asn Leu Leu Glu Met Ile Phe Met Ile 20 25 30 Thr Phe Val Val Ile Pro Phe Ser Trp Leu Arg Phe 35 40 229 41 PRT Homo sapien 229 Tyr Phe Pro Leu Gln Ile Trp Ile Ser Glu Asp Ser Asn Asn Ile Glu 1 5 10 15 Ala Val Asn Gln Trp Lys Glu Thr Val Ile Asn Pro Glu Lys Val Val 20 25 30 Ile Arg Trp His Lys Leu Asn Pro Ser 35 40 230 48 PRT Homo sapien 230 Met Leu Lys Gly His Tyr Gln Tyr Gly Met Glu Asp Leu Ser Phe His 1 5 10 15 Thr Phe Ser Ser Ser Phe Leu Asn Phe Leu Leu Leu Phe Leu Leu Ser 20 25 30 Cys Met Val Ala Pro Phe Pro Phe Leu Leu Ser Val Pro Ser Lys Gln 35 40 45 231 108 PRT Homo sapien 231 Phe Leu Lys Arg Gln Ser Ile Ser Leu Leu Pro Gln Leu Glu Cys Ser 1 5 10 15 Gly Thr Ile Ile Val His His Thr Leu Glu Leu Leu Gly Lys Gly Ser 20 25 30 Ser Leu Ala Ser Ala Ser Gln Val Ala Arg Tyr Thr Gly Met Cys Tyr 35 40 45 His Ala Trp Leu Ile Lys Lys Ile Phe Leu Glu Met Arg Ser Cys Cys 50 55 60 Val Ala Gln Ala Gly Leu Lys Leu Leu Gly Ser Asn Asn Pro Pro Thr 65 70 75 80 Leu Ala Ser Gln Ser Ala Gly Ile Thr Gly Val Ser His Ser Thr Ala 85 90 95 Pro Tyr Leu Gln Ile Leu Asn Gln Ala Ile Ala Ile 100 105 232 64 PRT Homo sapien 232 Met Ser Pro Arg Ala Pro Phe Ala Pro Gly Cys Pro Gln Pro Leu Val 1 5 10 15 Val Phe Tyr Val Cys Phe Phe Phe Phe Leu Ile Phe Cys Phe Val Lys 20 25 30 Lys His His Tyr Met Phe Leu Tyr Pro Arg Leu Lys Thr Phe Gly Asn 35 40 45 Leu Ile Ser Asn Ile Lys Ile Gln Ile Lys Thr His Ser Thr Ile Pro 50 55 60 233 35 PRT Homo sapien 233 Met Cys Val Asn Ala Ser Thr Val Gly Gln Met Cys Glu Asn Glu Leu 1 5 10 15 Lys His Met Leu Arg Ile Lys Val Asn Arg Arg Asn Phe Glu Arg Phe 20 25 30 Pro Leu Met 35 234 72 PRT Homo sapien 234 Met Asn Ile Phe Pro Trp Ala Gly Gly Pro Trp Ser Leu Pro Gln Ala 1 5 10 15 Arg Tyr Arg Ala Pro Ala Cys Ala Pro Thr Asn His Gly Lys Gln Arg 20 25 30 Arg Pro Pro His Leu Lys Ser Trp Pro Val Val Val Ser Ser Val Phe 35 40 45 Leu Leu Ser Glu Gln Asn Val Leu Lys Leu Glu Leu Thr Lys Val Lys 50 55 60 Ser Ser Lys Thr Thr Tyr Ala Thr 65 70 235 1163 PRT Homo sapien 235 Met Asp Arg Asn Arg Glu Ala Glu Met Glu Leu Arg Arg Gly Pro Ser 1 5 10 15 Pro Thr Arg Ala Gly Arg Gly His Glu Val Asp Gly Asp Lys Ala Thr 20 25 30 Cys His Thr Cys Cys Ile Cys Gly Lys Ser Phe Pro Phe Gln Ser Ser 35 40 45 Leu Ser Gln His Met Arg Lys His Thr Gly Glu Lys Pro Tyr Lys Cys 50 55 60 Pro Tyr Cys Asp His Arg Ala Ser Gln Lys Gly Asn Leu Lys Ile His 65 70 75 80 Ile Arg Ser His Arg Thr Gly Thr Leu Ile Gln Gly His Glu Pro Glu 85 90 95 Ala Gly Glu Ala Pro Leu Gly Glu Met Arg Ala Ser Glu Gly Leu Asp 100 105 110 Ala Cys Ala Ser Pro Thr Lys Ser Ala Ser Ala Cys Asn Arg Leu Leu 115 120 125 Asn Gly Ala Ser Gln Ala Asp Gly Ala Arg Val Leu Asn Gly Ala Ser 130 135 140 Gln Ala Asp Ser Gly Arg Val Leu Leu Arg Ser Ser Lys Lys Gly Ala 145 150 155 160 Glu Gly Ser Ala Cys Ala Pro Gly Glu Ala Lys Ala Ala Val Gln Cys 165 170 175 Ser Phe Cys Lys Ser Gln Phe Glu Arg Lys Lys Asp Leu Glu Leu His 180 185 190 Val His Gln Ala His Lys Pro Phe Lys Cys Arg Leu Cys Ser Tyr Ala 195 200 205 Thr Leu Arg Glu Glu Ser Leu Leu Ser His Ile Glu Arg Asp His Ile 210 215 220 Thr Ala Gln Gly Pro Gly Ser Gly Glu Ala Cys Val Glu Asn Gly Lys 225 230 235 240 Pro Glu Leu Ser Pro Gly Glu Phe Pro Cys Glu Val Cys Gly Gln Ala 245 250 255 Phe Ser Gln Thr Trp Phe Leu Lys Ala His Met Lys Lys His Arg Gly 260 265 270 Ser Phe Asp His Gly Cys His Ile Cys Gly Arg Arg Phe Lys Glu Pro 275 280 285 Trp Phe Leu Lys Asn His Met Lys Ala His Gly Pro Lys Thr Gly Ser 290 295 300 Lys Asn Arg Pro Lys Ser Glu Leu Asp Pro Ile Ala Thr Ile Asn Asn 305 310 315 320 Val Val Gln Glu Glu Val Ile Val Ala Gly Leu Ser Leu Tyr Glu Val 325 330 335 Cys Ala Lys Cys Gly Asn Leu Phe Thr Asn Leu Asp Ser Leu Asn Ala 340 345 350 His Asn Ala Ile His Arg Arg Val Glu Ala Ser Arg Thr Arg Ala Pro 355 360 365 Ala Glu Glu Gly Ala Glu Gly Pro Ser Asp Thr Lys Gln Phe Phe Leu 370 375 380 Gln Cys Leu Asn Leu Arg Pro Ser Ala Ala Gly Asp Ser Cys Pro Gly 385 390 395 400 Thr Gln Ala Gly Arg Arg Val Ala Glu Leu Asp Pro Val Asn Ser Tyr 405 410 415 Gln Ala Trp Gln Leu Ala Thr Arg Gly Lys Val Ala Glu Pro Ala Glu 420 425 430 Tyr Leu Lys Tyr Gly Ala Trp Asp Glu Ala Leu Ala Gly Asp Val Ala 435 440 445 Phe Asp Lys Asp Arg Arg Glu Tyr Val Leu Val Ser Gln Glu Lys Arg 450 455 460 Lys Arg Glu Gln Asp Ala Pro Ala Ala Gln Gly Pro Pro Arg Lys Arg 465 470 475 480 Ala Ser Gly Pro Gly Asp Pro Ala Pro Ala Gly His Leu Asp Pro Arg 485 490 495 Ser Ala Ala Arg Pro Asn Arg Arg Ala Ala Ala Thr Thr Gly Gln Gly 500 505 510 Lys Ser Ser Glu Cys Phe Glu Cys Gly Lys Ile Phe Arg Thr Tyr His 515 520 525 Gln Met Val Leu His Ser Arg Val His Arg Arg Ala Arg Arg Glu Arg 530 535 540 Asp Ser Asp Gly Asp Arg Ala Ala Arg Ala Arg Cys Gly Ser Leu Ser 545 550 555 560 Glu Gly Asp Ser Ala Ser Gln Pro Ser Ser Pro Gly Ser Ala Cys Ala 565 570 575 Ala Ala Asp Ser Pro Gly Ser Gly Leu Ala Asp Glu Ala Ala Glu Asp 580 585 590 Ser Gly Glu Glu Gly Ala Pro Glu Pro Ala Pro Gly Gly Gln Pro Arg 595 600 605 Arg Cys Cys Phe Ser Glu Glu Val Thr Ser Thr Glu Leu Ser Ser Gly 610 615 620 Asp Gln Ser His Lys Met Gly Asp Asn Ala Ser Glu Arg Asp Thr Gly 625 630 635 640 Glu Ser Lys Ala Gly Ile Ala Ala Ser Val Ser Ile Leu Glu Asn Ser 645 650 655 Ser Arg Glu Thr Ser Arg Arg Gln Glu Gln His Arg Phe Ser Met Asp 660 665 670 Leu Lys Met Pro Ala Phe His Pro Lys Gln Glu Val Pro Val Pro Gly 675 680 685 Asp Gly Val Glu Phe Pro Ser Ser Thr Gly Ala Glu Gly Gln Thr Gly 690 695 700 His Pro Ala Glu Lys Leu Ser Asp Leu His Asn Lys Glu His Ser Gly 705 710 715 720 Gly Gly Lys Arg Ala Leu Ala Pro Asp Leu Met Pro Leu Asp Leu Ser 725 730 735 Ala Arg Ser Thr Arg Asp Asp Pro Ser Asn Lys Glu Thr Ala Ser Ser 740 745 750 Leu Gln Ala Ala Leu Val Val His Pro Cys Pro Tyr Cys Ser His Lys 755 760 765 Thr Tyr Tyr Pro Glu Val Leu Trp Met His Lys Arg Ile Trp His Arg 770 775 780 Val Ser Cys Asn Ser Val Ala Pro Pro Trp Ile Gln Pro Asn Gly Tyr 785 790 795 800 Lys Ser Ile Arg Ser Asn Leu Val Phe Leu Ser Arg Ser Gly Arg Thr 805 810 815 Gly Pro Pro Pro Ala Leu Gly Gly Lys Glu Cys Gln Pro Leu Leu Leu 820 825 830 Ala Arg Phe Thr Arg Thr Gln Val Pro Gly Gly Met Pro Gly Ser Lys 835 840 845 Ser Gly Ser Ser Pro Leu Gly Val Val Thr Lys Ala Ala Ser Met Pro 850 855 860 Lys Asn Lys Glu Ser His Ser Gly Gly Pro Cys Ala Leu Trp Ala Pro 865 870 875 880 Gly Pro Asp Gly Tyr Arg Gln Thr Lys Pro Cys His Gly Gln Glu Pro 885 890 895 His Gly Ala Ala Thr Gln Gly Pro Leu Ala Lys Pro Arg Gln Glu Ala 900 905 910 Ser Ser Lys Pro Val Pro Ala Pro Gly Gly Gly Gly Phe Ser Arg Ser 915 920 925 Ala Thr Pro Thr Pro Thr Val Ile Ala Arg Ala Gly Ala Gln Pro Ser 930 935 940 Ala Asn Ser Lys Pro Val Glu Lys Phe Gly Val Pro Pro Ala Gly Ala 945 950 955 960 Gly Phe Ala Pro Thr Asn Lys His Ser Ala Pro Asp Ser Leu Lys Ala 965 970 975 Lys Phe Ser Ala Gln Pro Gln Gly Pro Pro Pro Ala Lys Gly Glu Gly 980 985 990 Gly Ala Pro Pro Leu Pro Pro Arg Glu Pro Pro Ser Lys Ala Ala Gln 995 1000 1005 Glu Leu Arg Thr Leu Ala Thr Cys Ala Ala Gly Ser Arg Gly Asp 1010 1015 1020 Ala Ala Leu Gln Ala Gln Pro Gly Val Ala Gly Ala Pro Pro Val 1025 1030 1035 Leu His Ser Ile Lys Gln Glu Pro Val Ala Glu Gly His Glu Lys 1040 1045 1050 Arg Leu Asp Ile Leu Asn Ile Phe Lys Thr Tyr Ile Pro Lys Asp 1055 1060 1065 Phe Ala Thr Leu Tyr Gln Gly Trp Gly Val Ser Gly Pro Gly Leu 1070 1075 1080 Glu His Arg Gly Thr Leu Arg Thr Gln Ala Arg Pro Gly Glu Phe 1085 1090 1095 Val Cys Ile Glu Cys Gly Lys Ser Phe His Gln Pro Gly His Leu 1100 1105 1110 Arg Ala His Met Arg Ala His Ser Val Val Phe Glu Ser Asp Gly 1115 1120 1125 Pro Arg Gly Ser Glu Val His Thr Thr Ser Ala Asp Ala Pro Lys 1130 1135 1140 Gln Gly Arg Asp His Ser Asn Thr Gly Thr Val Gln Thr Val Pro 1145 1150 1155 Leu Arg Lys Gly Thr 1160 236 55 PRT Homo sapien 236 Met Cys Val Phe Cys Gly Phe Phe Cys Ser Arg Phe Val Arg Glu Met 1 5 10 15 Trp Gly Asn Phe Gly Pro Lys Thr Asn Phe Thr Pro Gly Thr Pro Phe 20 25 30 Cys Pro Trp Leu Ser Pro Asn Leu Phe Cys Leu Val Val Val Trp Phe 35 40 45 Tyr Arg Leu Leu Ile Phe Tyr 50 55 237 156 PRT Homo sapien 237 Met Pro Met Glu Gly His Thr Leu Cys Met Arg Ile Arg Gly Ser Trp 1 5 10 15 Leu Ala Ala Arg Leu Pro Val Met Pro Phe Glu Gly Asp Val Gly Pro 20 25 30 Trp Val Arg Met Lys Val Phe Ile Cys His Ser Ser Ser Pro Gln Val 35 40 45 Ala Ile His Leu Gly Gly Gly Arg Glu Gly Ser Ala Leu Ala Ile Val 50 55 60 Tyr Pro Ala Ser Leu Arg Phe Ile Asp Leu His Lys Arg Leu Cys Ser 65 70 75 80 Gly Lys Gly Arg Gly Pro Gln Lys Gly Ala Trp Gln Asp Arg Trp Met 85 90 95 Leu Tyr Gly His Met Glu Ile Thr Pro Ser Ser Leu Ala Pro Ala Ser 100 105 110 Ala Ser Arg Pro Leu His Gly Val Arg Cys Phe Cys Ala Cys Cys Pro 115 120 125 Thr Ser Leu His Ser Arg Ala Leu Ile Asn His Phe Asp Pro Pro Leu 130 135 140 Ala Glu Gly Ser Pro Leu Tyr Arg Val Gln Ser Leu 145 150 155 238 86 PRT Homo sapien 238 Met Met Asn Phe Leu Cys Leu Asn Phe Arg Asp Ile Trp Cys Asp Phe 1 5 10 15 His Leu Tyr Leu Met Leu Pro Leu Leu Pro Ser Leu Leu Asn Thr Ser 20 25 30 Lys Asn Ser Glu His Ile Leu Ile Pro Pro Val Phe Tyr Phe Tyr Asp 35 40 45 Leu Asp Ile Leu His His Lys Ile Pro Pro Asn Trp Asp Tyr Val Phe 50 55 60 Glu Val Ile His Phe Thr Ile Ile Thr Thr Ile Thr Ile Ile Phe Ile 65 70 75 80 Val Cys Phe Val Pro Gly 85 239 289 PRT Homo sapien 239 Ala Asp Leu Ser Phe Ile Glu Asp Thr Val Ala Phe Pro Glu Lys Glu 1 5 10 15 Glu Asp Glu Glu Glu Glu Glu Glu Gly Val Glu Trp Gly Tyr Glu Glu 20 25 30 Gly Val Glu Trp Gly Leu Val Phe Pro Asp Ala Asn Gly Glu Tyr Gln 35 40 45 Ser Pro Ile Asn Leu Asn Ser Arg Glu Ala Arg Tyr Asp Pro Ser Leu 50 55 60 Leu Asp Val Arg Leu Ser Pro Asn Tyr Val Val Cys Arg Asp Cys Glu 65 70 75 80 Val Thr Asn Asp Gly His Thr Ile Gln Val Ile Leu Lys Ser Lys Ser 85 90 95 Val Leu Ser Gly Gly Pro Leu Pro Gln Gly His Glu Phe Glu Leu Tyr 100 105 110 Glu Val Arg Phe His Trp Gly Arg Glu Asn Gln Arg Gly Ser Glu His 115 120 125 Thr Val Asn Phe Lys Ala Phe Pro Met Glu Leu His Leu Ile His Trp 130 135 140 Asn Ser Thr Leu Phe Gly Ser Ile Asp Glu Ala Val Gly Lys Pro His 145 150 155 160 Gly Ile Ala Ile Ile Ala Leu Phe Val Gln Ile Gly Lys Glu His Val 165 170 175 Gly Leu Lys Ala Val Thr Glu Ile Leu Gln Asp Ile Gln Tyr Lys Gly 180 185 190 Lys Ser Lys Thr Ile Pro Cys Phe Asn Pro Asn Thr Leu Leu Pro Asp 195 200 205 Pro Leu Leu Arg Asp Tyr Trp Val Tyr Glu Gly Ser Leu Thr Ile Pro 210 215 220 Pro Cys Ser Glu Gly Val Thr Trp Ile Leu Phe Arg Tyr Pro Leu Thr 225 230 235 240 Ile Ser Gln Leu Gln Ile Glu Glu Phe Arg Arg Leu Arg Thr His Val 245 250 255 Lys Gly Ala Glu Leu Val Glu Gly Cys Asp Gly Ile Leu Gly Asp Asn 260 265 270 Phe Arg Pro Thr Gln Pro Leu Ser Asp Arg Val Ile Arg Ala Ala Phe 275 280 285 Gln 240 59 PRT Homo sapien 240 Met Cys Gln Ile Asp Arg Gln Asp Leu Val Leu Leu Lys Leu Val Ile 1 5 10 15 Tyr Cys Ser Arg His Leu Lys Gly Trp Arg Arg Ser Glu His Tyr Val 20 25 30 Pro Ala Arg Ala Ser Ile Thr Leu Arg Arg Ser Thr Ser His Leu Val 35 40 45 Ala Arg Ser Pro Asn Met Ser Ser Ser Gly Val 50 55 241 41 PRT Homo sapien 241 Met Leu Leu Asn Gly Leu His Asn Pro Ala Leu Lys His Leu Arg Asp 1 5 10 15 Leu Cys Lys Thr Phe Pro Trp Ser Leu Cys Phe Ser His Ile Asn Gln 20 25 30 Leu Ala Tyr Phe Ser His Ser Pro Ser 35 40 242 80 PRT Homo sapien 242 Met Asn Cys Leu Tyr Pro Ser Pro Met Cys Phe Tyr Arg Ser Cys Leu 1 5 10 15 Val His Phe Val Ala Asp Leu Leu Gly Asp Phe Thr Glu Gly Lys Val 20 25 30 Ser Ser Lys Leu Tyr Asp Asp Phe Met Leu Ile Asp Leu Leu Ser Ser 35 40 45 Gly Ser Trp Glu Thr His Ser Ala Ile Ser Leu Leu Ser Tyr Phe Ser 50 55 60 Tyr Asp Ala Gln Pro Pro Lys Ala Thr Arg Glu Gln Tyr Arg Val Pro 65 70 75 80 243 45 PRT Homo sapien 243 Glu Arg Pro Gly Met Leu Asp Phe Thr Gly Lys Ala Lys Trp Asp Ala 1 5 10 15 Trp Asn Glu Leu Lys Gly Thr Ser Lys Glu Asp Ala Met Lys Ala Tyr 20 25 30 Ile Asn Lys Val Glu Glu Leu Lys Lys Lys Tyr Gly Ile 35 40 45 244 24 PRT Homo sapien 244 Met Cys Leu Asn Phe Ser Phe Asn Tyr Leu Ile Pro Phe Ala Gln Glu 1 5 10 15 Ile Thr Ile Ser Leu Phe Phe Phe 20 245 69 PRT Homo sapien 245 Leu Phe Phe Gln Leu Phe Asp Thr Phe Cys Pro Arg Asp Tyr Tyr Leu 1 5 10 15 Ser Leu Phe Phe Phe Ser Phe Lys Thr Glu Cys Cys Ser Val Thr Gln 20 25 30 Val Gly Val Gln Trp His Asn Ser Ala Ser Leu Gln Pro Leu Pro Pro 35 40 45 Arg Leu Lys Arg Ser Ser His Leu Ser Leu Pro Ser Ser Trp Asp His 50 55 60 Arg His Ile Pro Pro 65 246 39 PRT Homo sapien 246 Met Glu Thr Lys His His Ser His Lys Lys Ser Asn Ser Ile Leu Asn 1 5 10 15 His Trp Lys Val Thr Ile Pro Leu Tyr Ser Phe Pro Lys Leu Phe Val 20 25 30 Ala Lys Ser Tyr Arg Lys Glu 35 247 93 PRT Homo sapien 247 Leu Leu Gln Ala Leu Lys Lys Ile Phe Phe Leu Asn Ser Leu Thr Leu 1 5 10 15 Ser Pro Arg Leu Glu Ala Ser Asn Val Ile Ser Ala His Cys Asn Leu 20 25 30 His Ser Arg Val Ala Gly Ile Thr Asp Met His His His Pro Gln Leu 35 40 45 Ile Phe Val Phe Leu Val Glu Thr Gly Phe Arg His Val Gly Gln Ala 50 55 60 Gly Leu Ala Leu Leu Ala Leu Arg Asp Pro Pro Pro Leu Ala Phe Gln 65 70 75 80 Ser Ala Gly Ile Thr Gly Val Ser His Cys Thr Trp Pro 85 90 248 51 PRT Homo sapien 248 Met Phe Phe Phe Phe Val Phe Phe Phe Phe Leu Phe Ala Arg Phe Ser 1 5 10 15 Arg Asn Val Gly Asp Leu Trp Ala Gly Lys Pro Phe Pro Pro Gly His 20 25 30 Val Leu Pro Arg Tyr Pro His Leu Phe Phe Phe Phe Phe Phe Phe Cys 35 40 45 Phe Ile Thr 50 249 62 PRT Homo sapien 249 Met Asn Phe Thr Leu Ala Ile Phe His Tyr Phe Ser Leu Ser Gln Met 1 5 10 15 Ser Val Leu Met Arg Gln Leu Ala Leu Thr Gly Ala Thr Leu Met Cys 20 25 30 His Leu Pro Thr Phe Asn Phe Trp Val Lys Ala Glu Arg Glu Lys Leu 35 40 45 Met Asp Phe Ser Phe Ser Arg Arg Asp Lys Asn Gln Leu His 50 55 60 250 190 PRT Homo sapien 250 Met Lys Leu Gln Leu Arg Ile Lys Ser Leu Thr Gln Asn Arg Thr Thr 1 5 10 15 Thr Trp Lys Leu Asn Asn Leu Leu Leu Asn Asp Tyr Trp Val Asn Lys 20 25 30 Lys Ile Lys Ala Glu Ile Asn Lys Phe Phe Glu Thr Ile Glu Asn Lys 35 40 45 Asp Thr Met Tyr Gln Asn Thr Ala Lys Ala Val Phe Arg Gly Lys Phe 50 55 60 Ile Ala Leu Asn Thr His Ile Arg Asn Trp Glu Ile Pro Lys Ile Asn 65 70 75 80 Val Leu Thr Ser Gln Leu Lys Glu Leu Glu Lys Arg Glu Gln Thr His 85 90 95 Ser Lys Gln Glu Ile Thr Lys Ile Ile Ala Glu Leu Lys Glu Ile Glu 100 105 110 Thr Gln Lys Ala Leu Gln Lys Ile Ser Asp Ser Arg Ser Trp Phe Phe 115 120 125 Glu Lys Ile Asn Lys Thr Asp Arg Leu Leu Ala Arg Ile Ile Lys Lys 130 135 140 Lys Arg Glu Lys Asn Gln Ile Asp Thr Ile Lys Asn Asp Lys Gly Asp 145 150 155 160 Ile Thr Thr Asn Pro Thr Glu Ile Gln Thr Ala Ile Arg Glu Cys Tyr 165 170 175 Gln His Leu Tyr Ile Asn Lys Leu Glu Asn Leu Glu Glu Ile 180 185 190 251 132 PRT Homo sapien 251 Met Pro Val Leu Ser Pro Pro Leu His Met Pro Tyr Pro Ala Ala Lys 1 5 10 15 Leu Asp Ser Val Leu Pro Asp Lys Thr Trp Tyr Trp His Leu Tyr Ala 20 25 30 Ser Val Cys Leu Pro Ser Thr Phe Lys Lys Pro Leu Gln Ser Ala Asp 35 40 45 Thr Lys Lys Gln Ser His Thr Cys Ser Lys Ser Ala Cys Phe Pro Leu 50 55 60 Ile Ser Ala Ser Cys Gln Arg His Cys Leu Thr Ser Ser Ser Leu Leu 65 70 75 80 Ser Ile Cys Val Pro His Lys Thr Leu Arg Asp Ser Ala Ser Tyr Val 85 90 95 Tyr Gly Leu Trp Val Phe Ile Ser Thr Val Pro Cys Leu Thr Leu Ser 100 105 110 Pro Cys Gly Glu Tyr Thr His Pro Thr Pro Thr Val Pro Cys Thr Ser 115 120 125 Val Ala Ala Gln 130 252 30 PRT Homo sapien 252 Met Gln Phe Arg Ile His Ala Ser Phe Ser Val Lys Trp Arg Ser Tyr 1 5 10 15 Ser Phe Asn Ser Glu Asn Ser Gln Leu Asn Lys Gln Pro Leu 20 25 30 253 49 PRT Homo sapien 253 Met Arg Val Val Trp Gly Trp Arg Cys Gly Cys Val Gly Val Leu Val 1 5 10 15 Leu Val Val Gly Gly Cys Val Glu Trp Ala Val Val Phe Gly Val Cys 20 25 30 Val Gly Cys Val Val Trp Val Gly Arg Trp Trp Cys Asp Val Val Val 35 40 45 Trp 254 54 PRT Homo sapien 254 Met Lys Lys Ser Val Ser Cys Cys Ser Ser Leu Trp Val Ser Leu Ser 1 5 10 15 Lys Asp Glu Asn Ala Glu Val Gly Arg Gly Asp Ser Leu Leu Gly Thr 20 25 30 Gly Arg Cys Gly Leu Pro Ile Thr Arg Leu Lys Leu Thr Ser Leu Pro 35 40 45 Ser Ser Pro Thr Val Val 50 255 1088 PRT Homo sapien 255 Asp Asp Ser Leu Ile Ser Ser Ala Thr Ala Ile Met Glu Ala Val Val 1 5 10 15 Arg Glu Trp Ile Leu Leu Glu Lys Gly Ser Ile Glu Ser Leu Arg Thr 20 25 30 Phe Leu Leu Thr Tyr Val Leu Gln Arg Pro Asn Leu Gln Lys Tyr Val 35 40 45 Arg Glu Gln Ile Leu Leu Ala Val Ala Val Ile Val Lys Arg Gly Ser 50 55 60 Leu Asp Lys Ser Ile Asp Cys Lys Ser Ile Phe His Glu Val Ser Gln 65 70 75 80 Leu Ile Ser Ser Gly Asn Pro Thr Val Gln Thr Leu Ala Cys Ser Ile 85 90 95 Leu Thr Ala Leu Leu Ser Glu Phe Ser Ser Ser Ser Lys Thr Ser Asn 100 105 110 Ile Gly Leu Ser Met Glu Phe His Gly Asn Cys Lys Arg Val Phe Gln 115 120 125 Glu Glu Asp Leu Arg Gln Ile Phe Met Leu Thr Val Glu Val Leu Gln 130 135 140 Glu Phe Ser Arg Arg Glu Asn Leu Asn Ala Gln Met Ser Ser Val Phe 145 150 155 160 Gln Arg Tyr Leu Ala Leu Ala Asn Gln Val Leu Ser Trp Asn Phe Leu 165 170 175 Pro Pro Asn Leu Gly Arg His Tyr Ile Ala Met Phe Glu Ser Ser Gln 180 185 190 Asn Val Leu Leu Lys Pro Thr Glu Ser Leu Arg Glu Thr Leu Leu Asp 195 200 205 Ser Arg Val Met Glu Leu Phe Phe Thr Val His Arg Lys Ile Arg Glu 210 215 220 His Ser Asp Met Ala Gln Asp Ser Leu Gln Cys Leu Ala Gln Leu Ala 225 230 235 240 Ser Leu His Gly Pro Ile Phe Pro Asp Glu Gly Ser Gln Val Asp Tyr 245 250 255 Leu Ala His Phe Ile Glu Gly Leu Leu Asn Thr Ile Asn Gly Ile Glu 260 265 270 Ile Glu Asp Ser Glu Ala Val Gly Ile Ser Ser Ile Ile Ser Asn Leu 275 280 285 Ile Thr Val Phe Pro Arg Asn Val Leu Thr Ala Ile Pro Ser Glu Leu 290 295 300 Phe Ser Ser Phe Val Asn Cys Leu Thr His Leu Thr Cys Ser Phe Gly 305 310 315 320 Arg Ser Ala Ala Leu Glu Glu Val Leu Asp Lys Asp Asp Met Val Tyr 325 330 335 Met Glu Ala Tyr Asp Lys Leu Leu Glu Ser Trp Leu Thr Leu Val Gln 340 345 350 Asp Asp Lys His Phe His Lys Gly Phe Phe Thr Gln His Ala Val Gln 355 360 365 Val Phe Asn Ser Tyr Ile Gln Cys His Leu Ala Ala Pro Asp Gly Thr 370 375 380 Arg Asn Leu Thr Ala Asn Gly Val Ala Ser Arg Glu Glu Glu Glu Ile 385 390 395 400 Ser Glu Leu Gln Glu Asp Asp Arg Asp Gln Phe Ser Asp Gln Leu Ala 405 410 415 Ser Val Gly Met Leu Gly Arg Ile Ala Ala Glu His Cys Ile Pro Leu 420 425 430 Leu Thr Ser Leu Leu Glu Glu Arg Val Thr Arg Leu His Gly Gln Leu 435 440 445 Gln Arg His Gln Gln Gln Leu Leu Ala Ser Pro Gly Ser Ser Thr Val 450 455 460 Asp Asn Lys Met Leu Asp Asp Leu Tyr Glu Asp Ile His Trp Leu Ile 465 470 475 480 Leu Val Thr Gly Tyr Leu Leu Ala Asp Asp Thr Gln Gly Glu Thr Pro 485 490 495 Leu Ile Pro Pro Glu Ile Met Glu Tyr Ser Ile Lys His Ser Ser Glu 500 505 510 Val Asp Ile Asn Thr Thr Leu Gln Ile Leu Gly Ser Pro Gly Glu Lys 515 520 525 Ala Ser Ser Ile Pro Gly Tyr Asn Arg Thr Asp Ser Val Ile Arg Leu 530 535 540 Leu Ser Ala Ile Leu Arg Val Ser Glu Val Glu Ser Arg Ala Ile Arg 545 550 555 560 Ala Asp Leu Thr His Leu Leu Ser Pro Gln Met Gly Lys Asp Ile Val 565 570 575 Trp Phe Leu Lys Arg Trp Ala Lys Thr Tyr Leu Leu Val Asp Glu Lys 580 585 590 Leu Tyr Asp Gln Ile Ser Leu Pro Phe Ser Thr Ala Phe Gly Ala Asp 595 600 605 Thr Glu Gly Ser Gln Trp Ile Ile Gly Tyr Leu Leu Gln Lys Val Ile 610 615 620 Ser Asn Leu Ser Val Trp Ser Ser Glu Gln Asp Leu Ala Asn Asp Thr 625 630 635 640 Val Gln Leu Leu Val Thr Leu Val Glu Arg Arg Glu Arg Ala Asn Leu 645 650 655 Val Ile Gln Cys Glu Asn Trp Trp Asn Leu Ala Lys Gln Phe Ala Ser 660 665 670 Arg Ser Pro Pro Leu Asn Phe Leu Ser Ser Pro Val Gln Arg Thr Leu 675 680 685 Met Lys Ala Leu Val Leu Gly Gly Phe Ala His Met Asp Thr Glu Thr 690 695 700 Lys Gln Gln Tyr Trp Thr Glu Val Leu Gln Pro Leu Gln Gln Arg Phe 705 710 715 720 Leu Arg Val Ile Asn Gln Glu Asn Phe Gln Gln Met Cys Gln Gln Glu 725 730 735 Glu Val Lys Gln Glu Ile Thr Ala Thr Leu Glu Ala Leu Cys Gly Ile 740 745 750 Ala Glu Ala Thr Gln Ile Asp Asn Val Ala Ile Leu Phe Asn Phe Leu 755 760 765 Met Asp Phe Leu Thr Asn Cys Ile Gly Leu Met Glu Val Tyr Lys Asn 770 775 780 Thr Pro Glu Thr Val Asn Leu Ile Ile Glu Val Phe Val Glu Val Ala 785 790 795 800 His Lys Gln Ile Cys Tyr Leu Gly Glu Ser Lys Ala Met Asn Leu Tyr 805 810 815 Glu Ala Cys Leu Thr Leu Leu Gln Val Tyr Ser Lys Asn Asn Leu Gly 820 825 830 Arg Gln Arg Ile Asp Val Thr Ala Glu Glu Glu Gln Tyr Gln Asp Leu 835 840 845 Leu Leu Ile Met Glu Leu Leu Thr Asn Leu Leu Ser Lys Glu Phe Ile 850 855 860 Asp Phe Ser Asp Thr Asp Glu Val Phe Arg Gly His Glu Pro Gly Gln 865 870 875 880 Ala Ala Asn Arg Ser Val Ser Ala Ala Asp Val Val Leu Tyr Gly Val 885 890 895 Asn Leu Ile Leu Pro Leu Met Ser Gln Asp Leu Leu Lys Phe Pro Thr 900 905 910 Leu Cys Asn Gln Tyr Tyr Lys Leu Ile Thr Phe Ile Cys Glu Ile Phe 915 920 925 Pro Glu Lys Ile Pro Gln Leu Pro Glu Asp Leu Phe Lys Ser Leu Met 930 935 940 Tyr Ser Leu Glu Leu Gly Met Thr Ser Met Ser Ser Glu Val Cys Gln 945 950 955 960 Leu Cys Leu Glu Ala Leu Thr Pro Leu Ala Glu Gln Cys Ala Lys Ala 965 970 975 Gln Glu Thr Asp Ser Pro Leu Phe Leu Ala Thr Arg His Phe Leu Lys 980 985 990 Leu Val Phe Asp Met Leu Val Leu Gln Lys His Asn Thr Glu Met Thr 995 1000 1005 Thr Ala Ala Gly Glu Ala Phe Tyr Thr Leu Val Cys Leu His Gln 1010 1015 1020 Ala Glu Tyr Ser Glu Leu Val Glu Thr Leu Leu Ser Ser Gln Gln 1025 1030 1035 Asp Pro Val Ile Tyr Gln Arg Leu Ala Asp Ala Phe Asn Lys Leu 1040 1045 1050 Thr Ala Ser Ser Thr Pro Pro Thr Leu Asp Arg Lys Gln Lys Met 1055 1060 1065 Ala Phe Leu Lys Ser Leu Glu Glu Phe Met Ala Asn Val Gly Gly 1070 1075 1080 Leu Leu Cys Val Lys 1085 256 78 PRT Homo sapien 256 Met Val Leu Met Thr Ser Ser Gly Gln Pro Ser Cys Pro Gly Ile Met 1 5 10 15 Ala Cys Gln His Ser Leu Cys Pro Pro Asn Leu Arg Pro Arg Met Arg 20 25 30 Ser Cys Gln His Asn Ile His Pro Phe Glu Gln Met Glu Ser Gly Thr 35 40 45 Leu Thr Gln Pro Ser Val Leu Asn Asn Thr Ala Ile Ile Ala Thr Trp 50 55 60 Leu Ser Arg Gln Cys Lys Pro Ser Glu Ser Ala Glu Leu Phe 65 70 75 257 595 PRT Homo sapien 257 Val Gln Lys Thr Asn Gln Cys Leu Gln Gly Gln Ser Leu Lys Thr Ser 1 5 10 15 Leu Thr Leu Lys Val Asp Arg Gly Ser Glu Glu Thr Tyr Arg Pro Glu 20 25 30 Phe Pro Ser Thr Lys Gly Leu Val Arg Ser Leu Ala Glu Gln Phe Gln 35 40 45 Arg Met Gln Gly Val Ser Met Arg Asp Ser Thr Gly Phe Lys Asp Arg 50 55 60 Ser Leu Ser Gly Ser Leu Arg Lys Asn Ser Ser Pro Ser Asp Ser Lys 65 70 75 80 Pro Pro Phe Ser Gln Gly Gln Glu Lys Gly His Trp Pro Trp Ala Lys 85 90 95 Gln Gln Ser Ser Leu Glu Gly Gly Asp Arg Pro Leu Ser Trp Glu Glu 100 105 110 Ser Thr Glu His Ser Ser Leu Ala Leu Asn Ser Gly Leu Pro Asn Gly 115 120 125 Glu Thr Ser Ser Gly Gly Gln Pro Arg Leu Ala Glu Pro Asp Ile Tyr 130 135 140 Gln Glu Lys Leu Ser Gln Val Arg Asp Val Arg Ser Lys Asp Leu Gly 145 150 155 160 Ser Ser Thr Asp Leu Gly Thr Ser Leu Pro Leu Asp Ser Trp Val Asn 165 170 175 Ile Thr Arg Phe Cys Asp Ser Gln Leu Lys His Gly Ala Pro Arg Pro 180 185 190 Gly Met Lys Ser Ser Pro His Asp Ser His Thr Cys Val Thr Tyr Pro 195 200 205 Glu Arg Asn His Ile Leu Leu His Pro His Trp Asn Gln Asp Thr Glu 210 215 220 Gln Glu Thr Ser Glu Leu Glu Ser Leu Tyr Gln Ala Ser Leu Gln Ala 225 230 235 240 Ser Gln Ala Gly Cys Ser Gly Trp Gly Gln Gln Asp Thr Ala Trp His 245 250 255 Pro Leu Ser Gln Thr Gly Ser Ala Asp Gly Met Gly Arg Arg Leu His 260 265 270 Ser Ala His Asp Pro Gly Leu Ser Lys Thr Ser Thr Ala Glu Met Glu 275 280 285 His Gly Leu His Glu Ala Arg Thr Val Arg Thr Ser Gln Ala Thr Pro 290 295 300 Cys Arg Gly Leu Ser Arg Glu Cys Gly Glu Asp Glu Gln Tyr Ser Ala 305 310 315 320 Glu Asn Leu Arg Arg Ile Ser Arg Ser Leu Ser Gly Thr Val Val Ser 325 330 335 Glu Arg Glu Glu Ala Pro Val Ser Ser His Ser Phe Asp Ser Ser Asn 340 345 350 Val Arg Lys Pro Leu Glu Thr Gly His Arg Cys Ser Ser Ser Ser Ser 355 360 365 Leu Pro Val Ile His Asp Pro Ser Val Phe Leu Leu Gly Pro Gln Leu 370 375 380 Tyr Leu Pro Gln Pro Gln Phe Leu Ser Pro Asp Val Leu Met Pro Thr 385 390 395 400 Met Ala Gly Glu Pro Asn Arg Leu Pro Gly Thr Ser Arg Ser Val Gln 405 410 415 Gln Phe Leu Ala Met Cys Asp Arg Gly Glu Thr Ser Gln Gly Ala Lys 420 425 430 Tyr Thr Gly Arg Thr Leu Asn Tyr Gln Ser Leu Pro His Arg Ser Arg 435 440 445 Thr Asp Asn Ser Trp Ala Pro Trp Ser Glu Thr Asn Gln His Ile Gly 450 455 460 Thr Arg Phe Leu Thr Thr Pro Gly Cys Asn Pro Gln Leu Thr Tyr Thr 465 470 475 480 Ala Thr Leu Pro Glu Arg Ser Lys Gly Leu Gln Val Pro His Thr Gln 485 490 495 Ser Trp Ser Asp Leu Phe His Ser Pro Ser His Pro Pro Ile Val His 500 505 510 Pro Val Tyr Pro Pro Ser Ser Ser Leu His Val Pro Leu Arg Ser Ala 515 520 525 Trp Asn Ser Asp Pro Val Pro Gly Ser Arg Thr Pro Gly Pro Arg Arg 530 535 540 Val Asp Met Pro Pro Asp Asp Asp Trp Arg Gln Ser Ser Tyr Ala Ser 545 550 555 560 His Ser Gly His Arg Arg Thr Val Gly Glu Gly Phe Leu Phe Val Leu 565 570 575 Ser Asp Ala Pro Arg Arg Glu Gln Ile Arg Ala Arg Val Leu Gln His 580 585 590 Ser Gln Trp 595 258 55 PRT Homo sapien 258 Met Thr Val Met Ile Leu Leu Phe Lys Lys Asn Pro Asn Cys Tyr Phe 1 5 10 15 Asp Leu Tyr Asp Leu Thr Leu Asn His Gly Ser Ile Thr Met Met Phe 20 25 30 Lys Thr Leu Ile Asp Ser Thr Cys Phe Lys Asn Ser Gln Ile Pro Ser 35 40 45 Ala Phe Ile Ile Arg Asp Arg 50 55 259 43 PRT Homo sapien 259 Met Met Leu Thr Met Glu Phe Lys Asn Lys Gln Gln His Phe Val Val 1 5 10 15 Ser Thr Gly Val Gly Val Glu Glu Leu Gln Arg His His Gly Asn Lys 20 25 30 Ser Leu Pro Arg Ile Ser Gly Pro Arg Asn Leu 35 40 260 75 PRT Homo sapien 260 Met Ala Tyr Arg Met Lys Arg Gly Thr Arg Asn Pro Cys Gly Arg Gly 1 5 10 15 Leu Asp Leu Lys Gln Cys Pro Leu Trp Leu Leu Leu Pro Trp Leu Thr 20 25 30 Gly Phe Leu Asp His Val His Phe Thr Gly Pro Trp Asp Leu His Leu 35 40 45 Leu Ala Ser Pro Ala Gly Leu Ile Pro Ala Arg Ala Pro Ser Phe Leu 50 55 60 Leu Met Val Phe Arg Trp Pro Asp His Gly Lys 65 70 75 261 218 PRT Homo sapien 261 Met Ile Asn His Leu Ser Pro His Gln Ala Ala Ala Pro Val Asp Gln 1 5 10 15 Thr Pro Arg Thr Leu Ala Thr Met Gly Gln Arg Ala Leu Pro Ser Ser 20 25 30 Leu Ala Leu Leu Ser Arg Pro Leu Ser Pro Pro Pro Ala Ala Cys Ser 35 40 45 Gly Asp Pro Gly Cys Gly Ser Gly Ala Gly Leu Pro Ser Ala Ser Ala 50 55 60 Ala Ala Gly Ile Ala Ser Ser Ala Val Glu Ala Val Cys Gly Asp Ala 65 70 75 80 Ala Pro Ala Cys Leu Leu Arg Thr Pro Leu Arg Gly Leu Leu Lys Pro 85 90 95 Thr Gly Pro Arg Ser Thr Met Glu Cys Pro Pro Ala Leu Ile Val Gln 100 105 110 Pro Pro Ala Gly Gly Met Ala Arg Arg Ala Ala Ser Gln Pro Trp Ala 115 120 125 Ala Ala Ser Ala Thr Pro Met Leu Ser Ser Lys Ala Ser Leu Cys Ile 130 135 140 Pro Thr Glu Arg Pro Pro Pro Gln Pro Leu Met Arg Thr Pro Ala Ala 145 150 155 160 Arg Ser His Trp Pro Ile Pro His Pro Ala Ser Thr Ala Cys Pro Ala 165 170 175 Pro Leu Pro Val Val Leu Val Ala Pro Arg Ser Thr Ile Leu Ser Met 180 185 190 Ser Arg Thr Trp Thr Cys Arg Arg Trp Ala Val Ala Pro Cys Arg Ala 195 200 205 Glu Lys Leu Met Cys Ser Ser Ser Arg Ser 210 215 262 104 PRT Homo sapien 262 Met Pro Ser Phe Phe Cys Phe Ser Ile Ser Leu Ile Arg Asp Trp Lys 1 5 10 15 Val Ser Ile Arg Ser Asn Thr Asp Phe Ile Val Ile Gly Thr Asn Cys 20 25 30 Ser Pro Thr Thr Pro Tyr Ser Ala Ser Ser Ile Thr Leu Leu Cys Glu 35 40 45 Ile Leu Arg Asn Gly Leu Pro Leu Gln Gly Leu Asn Leu Pro Tyr Leu 50 55 60 Arg Phe Glu Ser Ser Val Leu Phe Cys Ile Cys Phe Lys Tyr Leu Gly 65 70 75 80 Ser Val Thr His Ala Asn Met Thr Cys Pro Val Gln Ala Thr Leu Gly 85 90 95 Ile His Ile Ser His Val Ser Ser 100 263 260 PRT Homo sapien 263 Glu Lys Lys Lys Lys Met Lys Asn Glu Asn Ala Asp Lys Leu Leu Lys 1 5 10 15 Ser Glu Lys Gln Met Lys Lys Ser Glu Lys Lys Ser Lys Gln Glu Lys 20 25 30 Glu Lys Ser Lys Lys Lys Lys Gly Gly Lys Thr Glu Gln Asp Gly Tyr 35 40 45 Gln Lys Pro Thr Asn Lys His Phe Thr Gln Ser Pro Lys Lys Ser Val 50 55 60 Ala Asp Leu Leu Gly Ser Phe Glu Gly Lys Arg Arg Leu Leu Leu Ile 65 70 75 80 Thr Ala Pro Lys Ala Glu Asn Asn Met Tyr Val Gln Gln Arg Asp Glu 85 90 95 Tyr Leu Glu Ser Phe Cys Lys Met Ala Thr Arg Lys Ile Ser Val Ile 100 105 110 Thr Ile Phe Gly Pro Val Asn Asn Ser Thr Met Lys Ile Asp His Phe 115 120 125 Gln Leu Asp Asn Glu Lys Pro Met Arg Val Val Asp Asp Glu Asp Leu 130 135 140 Val Asp Gln Arg Leu Ile Ser Glu Leu Arg Lys Glu Tyr Gly Met Thr 145 150 155 160 Tyr Asn Asp Phe Phe Met Val Leu Thr Asp Val Asp Leu Arg Val Lys 165 170 175 Gln Tyr Tyr Glu Val Pro Ile Thr Met Lys Ser Val Phe Asp Leu Ile 180 185 190 Asp Thr Phe Gln Ser Arg Ile Lys Asp Met Glu Lys Gln Lys Lys Glu 195 200 205 Gly Ile Val Cys Lys Glu Asp Lys Lys Gln Ser Leu Glu Asn Phe Leu 210 215 220 Ser Arg Phe Arg Trp Arg Arg Arg Leu Leu Val Ile Ser Ala Pro Asn 225 230 235 240 Asp Glu Asp Trp Ala Tyr Ser Gln Gln Leu Ser Ala Leu Ser Gly Gln 245 250 255 Ala Cys Thr Leu 260 264 62 PRT Homo sapien 264 Met Ser Gly Phe Ile Tyr Val Leu Glu Lys Asp His Leu Lys Lys Ile 1 5 10 15 Asn Thr Phe Ser Thr Thr Lys Lys Lys Lys Lys Lys Lys Lys Lys Lys 20 25 30 Arg Arg Gly Gly Glu Pro Gly Ala Gln Ser Gly Pro Arg Gly Ala Asn 35 40 45 Trp Val Leu Pro Ala His Ile Pro Pro Lys Tyr Trp His Thr 50 55 60 265 89 PRT Homo sapien 265 Met Leu Gln Leu Asn Thr Arg Phe Tyr Phe Leu Ser Asn Cys Gly Phe 1 5 10 15 Val Phe Ile Tyr His Pro Leu Phe Ile Pro Phe Leu Thr His Thr Leu 20 25 30 Cys Arg Ala Ser Gly Ile Tyr Tyr Ser Thr Val Cys Leu Cys Lys Arg 35 40 45 Leu Ser Val Leu Ala Ser Thr Tyr Glu Arg Met His Ala Lys Phe Cys 50 55 60 Leu Ser Met Pro Gly Leu Ile Ser Leu Lys Gln Asn Asp Leu Arg Val 65 70 75 80 Pro Ser Met Leu Phe Ile Leu Pro Asn 85 266 38 PRT Homo sapien 266 Met Thr Ser Arg Trp Leu Asn Phe Ser Cys Leu Trp Cys Phe Gly Pro 1 5 10 15 Asn Ser Thr Gly Gln His His Asp His Met Glu Thr Tyr Phe Trp Lys 20 25 30 Gln Asn Phe Asn Phe Ile 35 267 111 PRT Homo sapien 267 Asn Asp Leu Asp Arg Tyr Asn Pro Leu Ser Ser Gln Arg Leu Val Arg 1 5 10 15 Asn Ala Leu Ala His Val Gly Ala Lys Glu Arg Glu Leu Ser Trp Ala 20 25 30 His Ser Glu Ser Phe Ala Ala Leu Cys Arg Tyr Gly Lys Arg Glu Phe 35 40 45 Lys Ile Gly Gly Glu Leu Arg Ile Gly Lys Gln Pro Tyr Arg Leu Gln 50 55 60 Ile Gln Leu Ser Ala Gln Arg Ser His Thr Leu Glu Phe Gln Ser Leu 65 70 75 80 Glu Asp Leu Ile Met Gly Glu Ala Thr Gln Arg Pro Arg Ser Gly Ala 85 90 95 Arg Pro Val Leu Gln Glu Leu Ala Thr His Leu His Pro Ala Glu 100 105 110 268 60 PRT Homo sapien 268 Met Val Asn Thr Val Leu Leu Ser Leu Lys Ile Ser Leu Phe Cys Pro 1 5 10 15 His Gln Leu Phe Tyr Cys Ser Val Leu Arg Lys Pro Asn Ser Cys Val 20 25 30 Phe Phe Pro Ser Leu Leu Ile Leu Ser Cys Val Pro Ser Gly Lys Cys 35 40 45 His Tyr Phe Leu Asp Ile Leu Asn Leu Leu Phe Leu 50 55 60 269 72 PRT Homo sapien 269 Met Cys Leu Cys Ile Leu Val Ser Lys Leu Arg Thr Ser Asp Glu Leu 1 5 10 15 Pro Val Val Pro Ser Tyr Cys Arg Arg Leu Glu Val Arg Gly Ile Ser 20 25 30 Ala Ser Thr Arg Glu Ala Glu Val Ala Ser Glu Pro Thr Ile Met Thr 35 40 45 Ala Cys Thr Pro Ser Leu Ala Thr Val Arg Glu Leu Leu Ser Gln Ile 50 55 60 Lys Arg Lys Gln Ser Leu Leu Ser 65 70 270 152 PRT Homo sapien 270 Gly Ser Leu Gly Gly Glu Pro Gly Val Ser Cys Leu Lys Met His Ser 1 5 10 15 Asp Ala Ala Ala Val Asn Phe Gln Leu Asn Ser His Leu Ser Thr Leu 20 25 30 Ala Asn Ile His Lys Ile Tyr His Thr Leu Asn Lys Leu Asn Leu Thr 35 40 45 Glu Asp Ile Gly Gln Asp Asp His Gln Thr Gly Ser Leu Arg Ser Cys 50 55 60 Ser Ser Ser Asp Cys Phe Asn Lys Val Met Pro Pro Arg Lys Lys Arg 65 70 75 80 Arg Pro Ala Ser Gly Asp Asp Leu Ser Ala Lys Lys Ser Arg His Asp 85 90 95 Ser Met Tyr Arg Lys Tyr Asp Ser Thr Arg Ile Lys Thr Glu Glu Glu 100 105 110 Ala Phe Ser Ser Lys Arg Cys Leu Glu Trp Phe Tyr Glu Tyr Ala Gly 115 120 125 Thr Asp Asp Val Val Gly Pro Glu Gly Met Glu Lys Phe Cys Glu Asp 130 135 140 Ile Gly Val Glu Pro Glu Asn Val 145 150 271 52 PRT Homo sapien 271 Met Glu Pro His Ile Met Lys Phe Asn Ser His Val Lys Thr Phe Cys 1 5 10 15 Ile Val Gly Cys Gln Lys Tyr Leu Pro Lys Leu Ser Phe Asp Leu Ser 20 25 30 Glu Trp Gly Trp Leu Leu Pro Ile Leu Gln Phe Val Ser Gln Ala Trp 35 40 45 Arg Asn Gln Ala 50 272 449 PRT Homo sapien 272 Met Val Met Glu Lys Pro Ser Pro Leu Leu Val Gly Arg Glu Phe Val 1 5 10 15 Arg Gln Tyr Tyr Thr Leu Leu Asn Lys Ala Pro Glu Tyr Leu His Arg 20 25 30 Phe Tyr Gly Arg Asn Ser Ser Tyr Val His Gly Gly Val Asp Ala Ser 35 40 45 Gly Lys Pro Gln Glu Ala Val Tyr Gly Gln Asn Asp Ile His His Lys 50 55 60 Val Leu Ser Leu Asn Phe Ser Glu Cys His Thr Lys Ile Arg His Val 65 70 75 80 Asp Ala His Ala Thr Leu Ser Asp Gly Val Val Val Gln Val Met Gly 85 90 95 Leu Leu Ser Asn Ser Gly Gln Pro Glu Arg Lys Phe Met Gln Thr Phe 100 105 110 Val Leu Ala Pro Glu Gly Ser Val Pro Asn Lys Phe Tyr Val His Asn 115 120 125 Asp Met Phe Arg Tyr Glu Asp Glu Val Phe Gly Asp Ser Glu Pro Glu 130 135 140 Leu Asp Glu Glu Ser Glu Asp Glu Val Glu Glu Glu Gln Glu Glu Arg 145 150 155 160 Gln Pro Ser Pro Glu Pro Val Gln Glu Asn Ala Asn Ser Gly Tyr Tyr 165 170 175 Glu Ala His Pro Val Thr Asn Gly Ile Glu Glu Pro Leu Glu Glu Ser 180 185 190 Ser His Glu Pro Glu Pro Glu Pro Glu Ser Glu Thr Lys Thr Glu Glu 195 200 205 Leu Lys Pro Gln Val Glu Glu Lys Asn Leu Glu Glu Leu Glu Glu Lys 210 215 220 Ser Thr Thr Pro Pro Pro Ala Glu Pro Val Ser Leu Pro Gln Glu Pro 225 230 235 240 Pro Lys Pro Arg Val Glu Ala Lys Pro Glu Val Gln Ser Gln Pro Pro 245 250 255 Arg Val Arg Glu Gln Arg Pro Arg Glu Arg Pro Gly Phe Pro Pro Arg 260 265 270 Gly Pro Arg Pro Gly Arg Gly Asp Met Glu Gln Asn Asp Ser Asp Asn 275 280 285 Arg Arg Ile Ile Arg Tyr Pro Asp Ser His Gln Leu Phe Val Gly Asn 290 295 300 Leu Pro His Asp Ile Asp Glu Asn Glu Leu Lys Glu Phe Phe Met Ser 305 310 315 320 Phe Gly Asn Val Val Glu Leu Arg Ile Asn Thr Lys Gly Val Gly Gly 325 330 335 Lys Leu Pro Asn Phe Gly Phe Val Val Phe Asp Asp Ser Glu Pro Val 340 345 350 Gln Arg Ile Leu Ile Ala Lys Pro Ile Met Phe Arg Gly Glu Val Arg 355 360 365 Leu Asn Val Glu Glu Lys Lys Thr Arg Ala Ala Arg Glu Arg Glu Thr 370 375 380 Arg Gly Gly Gly Asp Asp Arg Arg Asp Ile Arg Arg Asn Asp Arg Gly 385 390 395 400 Pro Gly Gly Pro Arg Gly Ile Val Gly Gly Gly Met Met Arg Asp Arg 405 410 415 Asp Gly Arg Gly Pro Pro Pro Arg Gly Gly Met Ala Gln Lys Leu Gly 420 425 430 Ser Gly Arg Gly Thr Gly Gln Met Glu Gly Arg Phe Thr Gly Gln Arg 435 440 445 Arg 273 63 PRT Homo sapien 273 Met Cys Cys Asp Val Ser Glu Arg Ala Glu Phe Arg Leu Val Ser Ala 1 5 10 15 Arg Cys Ser Phe Ser His Pro Arg Thr Val Ala Arg Leu Leu Leu Arg 20 25 30 His Pro Gly Gln Leu Pro Leu Pro Phe Gln Trp Gly Leu Thr Trp Leu 35 40 45 Pro Ser Leu Ala Ala Asn Arg Arg Ala Pro Gln His Ser Arg Ser 50 55 60 274 60 PRT Homo sapien 274 Met Asp Pro Gly Arg Tyr Cys Leu Val Leu Gln Glu Leu Met Gln Phe 1 5 10 15 His Ser Glu Ala Cys Lys Ile Leu Asn Phe Arg Asp Asn Arg Pro Asp 20 25 30 Thr Phe Leu Ile Ser Phe Tyr Ser Leu Met Ser Asn Asn Thr Ile Phe 35 40 45 Lys Asn Met Val Leu Ile Cys Leu Ala Ser Asn Leu 50 55 60 275 111 PRT Homo sapien 275 Lys Leu Ile Val Tyr Pro Pro Pro Pro Ala Lys Gly Gly Ile Ser Val 1 5 10 15 Thr Asn Glu Asp Leu His Cys Leu Asn Glu Gly Glu Phe Leu Asn Asp 20 25 30 Val Ile Ile Asp Phe Tyr Leu Lys Tyr Leu Val Leu Glu Lys Leu Lys 35 40 45 Lys Glu Asp Ala Asp Arg Ile His Ile Phe Ser Ser Phe Phe Tyr Lys 50 55 60 Arg Leu Asn Gln Arg Glu Arg Arg Asn His Glu Thr Thr Asn Leu Ser 65 70 75 80 Ile Gln Gln Lys Arg His Gly Arg Val Lys Thr Trp Thr Arg His Val 85 90 95 Asp Ile Phe Glu Lys Asp Phe Ile Phe Val Pro Leu Asn Glu Ala 100 105 110 276 97 PRT Homo sapien 276 Met Ser Gln Asp Thr Ser Arg Ser Gln Glu Arg Ala Ala Gly Pro Gln 1 5 10 15 Arg Thr Arg Arg Arg Pro Arg Thr Trp Ser Gly Gly Val Glu Pro Thr 20 25 30 Ala Ala Ala Pro Trp Ala Ala Ala Met Ala His Thr Gly Arg His Gly 35 40 45 Ser Gly Ala Ala Ala Thr Ala Ser Ser Thr Arg Gly Asp Gly Ala Ala 50 55 60 Arg Arg Gly Ala Ala Arg Gly Thr Asp Ala Ala Glu Arg Arg Arg Ala 65 70 75 80 Ala Ser Arg Gly Ala Ala Glu Pro Lys Ala Thr Ala Ser Gly Gly Gly 85 90 95 Gly 277 76 PRT Homo sapien 277 Met Gly Ser Cys Pro Leu Trp Val Arg Ser Ser Thr Cys Arg Val Glu 1 5 10 15 Val Gly Tyr Val His Thr Phe Asn Asp Asn Leu His Ile Ser Ala Pro 20 25 30 Thr Gly Pro Lys Leu Phe Leu Gly Phe Lys Val Val Val Cys Leu Phe 35 40 45 Phe Ser Phe Phe Phe Phe Phe Phe Phe Phe Gly Glu Val Glu Phe Gly 50 55 60 Ser Gly Trp Pro Arg Cys Gly Val Cys Lys Gly Arg 65 70 75 278 20 PRT Homo sapien 278 Met Glu Asp Gln Ile Ile Leu Asn Tyr Ile Ser Ile Val Pro Gly Lys 1 5 10 15 Thr Gln Val Leu 20 279 24 PRT Homo sapien 279 Met Val His Leu Met His Ala Arg Ala Arg Ala Ser Cys Asp Gly Cys 1 5 10 15 Val Val Ala Ala Glu Val His Val 20 280 101 PRT Homo sapien 280 Leu Phe Phe Phe Lys Lys Phe Ile Leu Arg Trp Ser Leu Thr Leu Ser 1 5 10 15 Leu Arg Leu Glu Cys Ser Asp Ser Ile Ser Ala His Cys Asn Leu Arg 20 25 30 Leu Pro Gly Leu Ser Asn Phe Cys Ala Ser Ala Ser Gln Val Ser Glu 35 40 45 Ile Thr Gly Val Cys His His Thr Gln Leu Phe Phe Ile Phe Tyr Phe 50 55 60 Ala Ala Lys Met Gly Phe Arg His Val Gly Arg Thr Gly Leu Glu Leu 65 70 75 80 Leu Ala Ser Ser Gly Pro Pro Thr Ser Ala Ser Gln Ser Ala Gly Ile 85 90 95 Thr Gly Val Ser His 100 281 43 PRT Homo sapien 281 Met Trp Gly His Gly Leu Asp Asp Gly Leu His Arg Ser Phe His Leu 1 5 10 15 Cys Glu Ser Lys Ser Gly Gln Ser Ala Arg Thr Gln Ser Leu Thr Leu 20 25 30 Gly Gln Leu Leu Arg Thr Asn Pro Gln His Leu 35 40 282 46 PRT Homo sapien 282 Met Ala Gly Asn Ile His Pro Gly Thr Phe Gly Pro Gly Ser Pro His 1 5 10 15 Leu Phe Phe Leu Cys Gly Val Val Ala Phe Phe Leu Phe Ile Val Ala 20 25 30 Arg Glu Ala Lys Ile Tyr Ser Phe Ser Met Asn Pro Asn Met 35 40 45 283 70 PRT Homo sapien 283 Met Pro Gly Ser His Leu Cys Met Phe Asn Thr Val Thr His Asp Val 1 5 10 15 Ile Thr Glu Trp Arg Arg Trp Lys Gly Pro Cys Arg Ser Phe Ser Trp 20 25 30 His Pro Asn Phe Thr Glu Gly Glu Leu Arg Pro Glu Leu Arg Asp Val 35 40 45 Leu Arg Ile Pro Glu Ser His Ser Ser Val Arg Ser Val Ile His Lys 50 55 60 Glu Val Ile Ile Lys Val 65 70 284 49 PRT Homo sapien 284 Met Ser Ser Ser Leu Phe Ala Phe Leu Leu Thr Tyr Phe Val Val Phe 1 5 10 15 Lys Asp Cys Ala Gly Asp Ile Leu Glu Gly Ile Asn Gly Leu His Ser 20 25 30 Lys Arg Cys Gly Leu Ser Lys Leu Phe Ser Val Phe Ile Thr Glu Thr 35 40 45 Asp 285 1544 PRT Homo sapien 285 Met Tyr Ala Ala Val Glu His Gly Pro Val Leu Cys Ser Asp Ser Asn 1 5 10 15 Ile Leu Cys Leu Ser Trp Lys Gly Arg Val Pro Lys Ser Glu Lys Glu 20 25 30 Lys Pro Val Cys Arg Arg Arg Tyr Tyr Glu Glu Gly Trp Leu Ala Thr 35 40 45 Gly Asn Gly Arg Gly Val Val Gly Val Thr Phe Thr Ser Ser His Cys 50 55 60 Arg Arg Asp Arg Ser Thr Pro Gln Arg Ile Asn Phe Asn Leu Arg Gly 65 70 75 80 His Asn Ser Glu Val Val Leu Val Arg Trp Asn Glu Pro Tyr Gln Lys 85 90 95 Leu Ala Thr Cys Asp Ala Asp Gly Gly Ile Phe Val Trp Ile Gln Tyr 100 105 110 Glu Gly Arg Trp Ser Val Glu Leu Val Asn Asp Arg Gly Ala Gln Val 115 120 125 Ser Asp Phe Thr Trp Ser His Asp Gly Thr Gln Ala Leu Ile Ser Tyr 130 135 140 Arg Asp Gly Phe Val Leu Val Gly Ser Val Ser Gly Gln Arg His Trp 145 150 155 160 Ser Ser Glu Ile Asn Leu Glu Ser Gln Ile Thr Cys Gly Ile Trp Thr 165 170 175 Pro Asp Asp Gln Gln Val Leu Phe Gly Thr Ala Asp Gly Gln Val Ile 180 185 190 Val Met Asp Cys His Gly Arg Met Leu Ala His Val Leu Leu His Glu 195 200 205 Ser Asp Gly Val Leu Gly Met Ser Trp Asn Tyr Pro Ile Phe Leu Val 210 215 220 Glu Asp Ser Ser Glu Ser Asp Thr Asp Ser Asp Asp Tyr Ala Pro Pro 225 230 235 240 Gln Asp Gly Pro Ala Ala Tyr Pro Ile Pro Val Gln Asn Ile Lys Pro 245 250 255 Leu Leu Thr Val Ser Phe Thr Ser Gly Asp Ile Ser Leu Met Asn Asn 260 265 270 Tyr Asp Asp Leu Ser Pro Thr Val Ile Arg Ser Gly Leu Lys Glu Val 275 280 285 Val Ala Gln Trp Cys Thr Gln Gly Asp Leu Leu Ala Val Ala Gly Met 290 295 300 Glu Arg Gln Thr Gln Leu Gly Glu Leu Pro Asn Gly Pro Leu Leu Lys 305 310 315 320 Ser Ala Met Val Lys Phe Tyr Asn Val Arg Gly Glu His Ile Phe Thr 325 330 335 Leu Asp Thr Leu Val Gln Arg Pro Ile Ile Ser Ile Cys Trp Gly His 340 345 350 Arg Asp Ser Arg Leu Leu Met Ala Ser Gly Pro Ala Leu Tyr Val Val 355 360 365 Arg Val Glu His Arg Val Ser Ser Leu Gln Leu Leu Cys Gln Gln Ala 370 375 380 Ile Ala Ser Thr Leu Arg Glu Asp Lys Asp Val Ser Lys Leu Thr Leu 385 390 395 400 Pro Pro Arg Leu Cys Ser Tyr Leu Ser Thr Ala Phe Ile Pro Thr Ile 405 410 415 Lys Pro Pro Ile Pro Asp Pro Asn Asn Met Arg Asp Phe Val Ser Tyr 420 425 430 Pro Ser Ala Gly Asn Glu Arg Leu His Cys Thr Met Lys Arg Thr Glu 435 440 445 Asp Asp Pro Glu Val Gly Gly Pro Cys Tyr Thr Leu Tyr Leu Glu Tyr 450 455 460 Leu Gly Gly Leu Val Pro Ile Leu Lys Gly Arg Arg Ile Ser Lys Leu 465 470 475 480 Arg Pro Glu Phe Val Ile Met Asp Pro Arg Thr Asp Ser Lys Pro Asp 485 490 495 Glu Ile Tyr Gly Asn Ser Leu Ile Ser Thr Val Ile Asp Ser Cys Asn 500 505 510 Cys Ser Asp Ser Ser Asp Ile Glu Leu Ser Asp Asp Trp Ala Ala Lys 515 520 525 Lys Ser Pro Lys Ile Ser Arg Ala Ser Lys Ser Pro Lys Leu Pro Arg 530 535 540 Ile Ser Ile Glu Ala Arg Lys Ser Pro Lys Leu Pro Arg Ala Ala Gln 545 550 555 560 Glu Leu Ser Arg Ser Pro Arg Leu Pro Leu Arg Lys Pro Ser Val Gly 565 570 575 Ser Pro Ser Leu Thr Arg Arg Glu Phe Pro Phe Glu Asp Ile Thr Gln 580 585 590 His Asn Tyr Leu Ala Gln Val Thr Ser Asn Ile Trp Gly Thr Lys Phe 595 600 605 Lys Ile Val Gly Leu Ala Ala Phe Leu Pro Thr Asn Leu Gly Ala Val 610 615 620 Ile Tyr Lys Thr Ser Leu Leu His Leu Gln Pro Arg Gln Met Thr Ile 625 630 635 640 Tyr Leu Pro Glu Val Arg Lys Ile Ser Met Asp Tyr Ile Asn Leu Pro 645 650 655 Val Phe Asn Pro Asn Val Phe Ser Glu Asp Glu Asp Asp Leu Pro Val 660 665 670 Thr Gly Ala Ser Gly Val Pro Glu Asn Ser Pro Pro Cys Thr Val Asn 675 680 685 Ile Pro Ile Ala Pro Ile His Ser Ser Ala Gln Ala Met Ser Pro Thr 690 695 700 Gln Ser Ile Gly Leu Val Gln Ser Leu Leu Ala Asn Gln Asn Val Gln 705 710 715 720 Leu Asp Val Leu Thr Asn Gln Thr Thr Ala Val Gly Thr Ala Glu His 725 730 735 Ala Gly Asp Arg Cys His Pro Val Thr Gln Val Ser Asn Arg Tyr Ser 740 745 750 Asn Pro Gly Gln Val Ile Phe Gly Ser Val Glu Met Gly Arg Ile Ile 755 760 765 Gln Asn Pro Pro Pro Leu Ser Leu Pro Pro Pro Pro Gln Gly Pro Met 770 775 780 Gln Leu Ser Thr Val Gly His Gly Asp Arg Asp His Glu His Leu Gln 785 790 795 800 Lys Ser Ala Lys Ala Leu Arg Pro Thr Pro Gln Leu Ala Ala Glu Gly 805 810 815 Asp Ala Val Val Phe Ser Ala Pro Gln Glu Val Gln Val Thr Lys Ile 820 825 830 Asn Pro Pro Pro Pro Tyr Pro Gly Thr Ile Pro Ala Ala Pro Thr Thr 835 840 845 Ala Ala Pro Pro Pro Pro Leu Pro Pro Pro Gln Pro Pro Val Asp Val 850 855 860 Cys Leu Lys Lys Gly Asp Phe Ser Leu Tyr Pro Thr Ser Val His Tyr 865 870 875 880 Gln Thr Pro Leu Gly Tyr Glu Arg Ile Thr Thr Phe Asp Ser Ser Gly 885 890 895 Asn Val Glu Glu Val Cys Arg Pro Arg Thr Arg Met Leu Cys Ser Gln 900 905 910 Asn Thr Tyr Thr Leu Pro Gly Pro Gly Ser Ser Ala Thr Leu Arg Leu 915 920 925 Thr Ala Thr Glu Lys Lys Val Pro Gln Pro Cys Ser Ser Ala Thr Leu 930 935 940 Asn Arg Leu Thr Val Pro Arg Tyr Ser Ile Pro Thr Gly Asp Pro Pro 945 950 955 960 Pro Tyr Pro Glu Ile Ala Ser Gln Leu Ala Gln Gly Arg Gly Ala Ala 965 970 975 Gln Arg Ser Asp Asn Ser Leu Ile His Ala Thr Leu Arg Arg Asn Asn 980 985 990 Arg Glu Ala Thr Leu Lys Met Ala Gln Leu Ala Asp Ser Pro Arg Ala 995 1000 1005 Pro Leu Gln Pro Leu Ala Lys Ser Lys Gly Gly Pro Gly Gly Val 1010 1015 1020 Val Thr Gln Leu Pro Ala Arg Pro Pro Pro Ala Leu Tyr Thr Cys 1025 1030 1035 Ser Gln Cys Ser Gly Thr Gly Pro Ser Ser Gln Pro Gly Ala Ser 1040 1045 1050 Leu Ala His Thr Ala Ser Ala Ser Pro Leu Ala Ser Gln Ser Ser 1055 1060 1065 Tyr Ser Leu Leu Ser Pro Pro Asp Ser Ala Arg Asp Arg Thr Asp 1070 1075 1080 Tyr Val Asn Ser Ala Phe Thr Glu Asp Glu Ala Leu Ser Gln His 1085 1090 1095 Cys Gln Leu Glu Lys Pro Leu Arg His Pro Pro Leu Pro Glu Ala 1100 1105 1110 Ala Val Thr Leu Lys Arg Pro Pro Pro Tyr Gln Trp Asp Pro Met 1115 1120 1125 Leu Gly Glu Asp Val Trp Val Pro Gln Glu Arg Thr Ala Gln Thr 1130 1135 1140 Ser Gly Pro Asn Pro Leu Lys Leu Ser Ser Leu Met Leu Ser Gln 1145 1150 1155 Gly Gln His Leu Asp Val Ser Arg Leu Pro Phe Ile Ser Pro Lys 1160 1165 1170 Ser Pro Ala Ser Pro Thr Ala Thr Phe Gln Thr Gly Tyr Gly Met 1175 1180 1185 Gly Val Pro Tyr Pro Gly Ser Tyr Asn Asn Pro Pro Leu Pro Gly 1190 1195 1200 Val Gln Ala Pro Cys Ser Pro Lys Asp Ala Leu Ser Pro Thr Gln 1205 1210 1215 Phe Ala Gln Gln Glu Pro Ala Val Val Leu Gln Pro Leu Tyr Pro 1220 1225 1230 Pro Ser Leu Ser Tyr Cys Thr Leu Pro Pro Met Tyr Pro Gly Ser 1235 1240 1245 Ser Thr Cys Ser Ser Leu Gln Leu Pro Pro Val Ala Leu His Pro 1250 1255 1260 Trp Ser Ser Tyr Ser Ala Cys Pro Pro Met Gln Asn Pro Gln Gly 1265 1270 1275 Thr Leu Pro Pro Lys Pro His Leu Val Val Glu Lys Pro Leu Val 1280 1285 1290 Ser Pro Pro Pro Ala Asp Leu Gln Ser His Leu Gly Thr Glu Val 1295 1300 1305 Met Val Glu Thr Ala Asp Asn Phe Gln Glu Val Leu Ser Leu Thr 1310 1315 1320 Glu Ser Pro Val Pro Gln Arg Thr Glu Lys Phe Gly Lys Lys Asn 1325 1330 1335 Arg Lys Arg Leu Asp Ser Arg Ala Glu Glu Gly Ser Val Gln Ala 1340 1345 1350 Ile Thr Glu Gly Lys Val Lys Lys Glu Ala Arg Thr Leu Ser Asp 1355 1360 1365 Phe Asn Ser Leu Ile Ser Ser Pro His Leu Gly Arg Glu Lys Lys 1370 1375 1380 Lys Val Lys Ser Gln Lys Asp Gln Leu Lys Ser Lys Lys Leu Asn 1385 1390 1395 Lys Thr Asn Glu Phe Gln Asp Ser Ser Glu Ser Glu Pro Glu Leu 1400 1405 1410 Phe Ile Ser Gly Asp Glu Leu Met Asn Gln Ser Gln Gly Ser Arg 1415 1420 1425 Lys Gly Trp Lys Ser Lys Arg Ser Pro Arg Ala Ala Gly Glu Leu 1430 1435 1440 Glu Glu Ala Lys Cys Arg Arg Ala Ser Glu Lys Glu Asp Gly Arg 1445 1450 1455 Leu Gly Ser Gln Gly Phe Val Tyr Val Met Ala Asn Lys Gln Pro 1460 1465 1470 Leu Trp Asn Glu Ala Thr Gln Val Tyr Gln Leu Asp Phe Gly Gly 1475 1480 1485 Arg Val Thr Gln Glu Ser Ala Lys Asn Phe Gln Ile Glu Leu Glu 1490 1495 1500 Gly Arg Gln Val Met Gln Phe Gly Arg Ile Asp Gly Ser Ala Tyr 1505 1510 1515 Ile Leu Asp Phe Gln Tyr Pro Phe Ser Ala Val Gln Ala Phe Ala 1520 1525 1530 Val Ala Leu Ala Asn Val Thr Gln Arg Leu Lys 1535 1540 286 56 PRT Homo sapien 286 Met Gly Asn Gly Ala Thr Gln Lys Gln Leu Pro Asn Leu Arg Asn Asn 1 5 10 15 Ser Phe Val Val Tyr Phe Leu Val Leu Val Gly Ala Leu Tyr Arg Asp 20 25 30 Thr Ala Ile Phe Leu Ala Gln Met Ser Leu Leu Glu Ser Thr Val Val 35 40 45 Ile Leu Leu Val Arg Leu Arg Thr 50 55 287 77 PRT Homo sapien 287 Met Leu Leu Ala Val Arg Thr Thr Val Ile Cys Leu Gln Ser Cys Cys 1 5 10 15 Cys Arg Ile Gln Arg Thr Ala Thr Ile Thr Leu Asn Cys Phe Ala Leu 20 25 30 Ser Ser Ile Phe Asp Tyr Tyr Ile Ser His Asn Ile Thr Ile Ser His 35 40 45 Ser Ser Asn Tyr Ser Ala Gln Ile His Glu His Val Pro Ala Arg Ala 50 55 60 Ala Ala Arg Ser Ile Thr Trp Arg Arg Ser Ala Cys Ile 65 70 75 288 45 PRT Homo sapien 288 Met Tyr Leu Gly Gln Leu Gly Asn His Arg Leu Lys Lys Leu Thr Leu 1 5 10 15 Val Ile Thr Arg Val Val Ser Asp Tyr Lys Gln His Ile Ile Asn Pro 20 25 30 Thr Ala Leu Ile Leu Ala Gln Arg Gln Asn Trp Thr Phe 35 40 45 289 44 PRT Homo sapien 289 Met Lys Ala Leu Leu Cys Phe Leu Phe Tyr Ser Asp His Gln Thr Asp 1 5 10 15 Leu Ala Thr Leu Ile Val Lys Asn Glu Pro His Ser Ser Pro Gly Leu 20 25 30 Gly Leu Trp Arg Glu Met Asn Phe Leu Leu Glu Met 35 40 290 50 PRT Homo sapien 290 Met Phe Arg Thr Ser Ser Tyr Arg Leu Leu Ile Tyr Lys Val Pro Val 1 5 10 15 Ala Val Thr Pro Thr Arg Lys Thr Trp Asn Cys Lys Gln Ala Gly Val 20 25 30 Thr Ser Val Thr Ser Asp Thr Val Gln Pro Glu Val Arg Phe Leu Phe 35 40 45 Trp Gly 50 291 44 PRT Homo sapien 291 Met Ser Gln Trp Pro Val Ala Ser Lys Leu Val Gly Lys Glu Lys Thr 1 5 10 15 Phe Leu Phe Lys Gln Arg Lys Gly Phe Gly Glu Lys Thr Gly Ser Gly 20 25 30 Ser Gly Glu Val Phe Val Met Leu Gly Asp Arg Leu 35 40 292 61 PRT Homo sapien 292 Met Val His Tyr Arg Lys Glu Lys Lys Thr Ser Val Ser Glu Trp Gln 1 5 10 15 Ile Leu Ile Ile Cys Ser Ser His Leu Phe Ser Ser Glu Asn His Ile 20 25 30 Thr Pro Glu Tyr Leu Pro Gly Arg Ile His His Thr Ala Pro Leu Glu 35 40 45 Pro Ala Ser Lys Asp Pro Phe Ala His Ile Val Ile Leu 50 55 60 293 112 PRT Homo sapien 293 Met Gly Ile Ile Leu Asn Trp Leu Asn Gln Trp Ala Gln Ile Thr Tyr 1 5 10 15 Leu Pro Ser Leu Leu Cys Asp Ser Pro Ala Val Thr His Thr Ile His 20 25 30 Ile Leu Cys Thr Ser Asn Glu Gln Thr Trp Phe Pro Cys Phe Leu Asp 35 40 45 Ile Ser Met Thr Val Ser His Thr Asn Tyr Trp Val Arg Phe Phe Ser 50 55 60 Cys Tyr Arg Pro Thr Ser Cys Cys Leu Cys Val Val Leu Gln Lys Leu 65 70 75 80 Ser Ile Pro Thr Pro Leu Leu Cys His Leu Gln Glu Ser Gly Ile Val 85 90 95 Arg Ser Gln Leu Arg Lys Val Leu Val Pro Leu Thr Gly His Ile Leu 100 105 110 294 55 PRT Homo sapien 294 Met Arg Phe Ile Phe Ile Cys Lys Pro Arg Gly Leu Ile Ile Leu Ile 1 5 10 15 Leu Tyr Glu Tyr Thr Cys Val Leu Gly Lys Ala Phe Ile Gln Gln Met 20 25 30 Pro Thr Thr Tyr Ser Val Pro Arg Pro Arg His Pro Val Thr Ser Trp 35 40 45 Arg Pro Ala Arg Ala Cys Ile 50 55 295 77 PRT Homo sapien 295 Met Leu Glu Leu Pro Thr Phe Ser Phe Phe Phe Phe Gly Asp Arg Ala 1 5 10 15 Ser Leu Cys His Pro Gly Trp Ser Ala Gly Ala Ser Ser Leu Thr His 20 25 30 Leu Gln Pro Ser Phe Leu Pro Trp Gly Ala Gly Arg Phe Ser Cys Ala 35 40 45 Leu Gln Pro Pro Ser Leu Ala Gly Ile Tyr Arg Ala Leu Leu Gln Val 50 55 60 Ser His Ile Phe Ser Glu Lys Phe Leu Asn Trp Pro Pro 65 70 75 

We claim:
 1. An isolated nucleic acid molecule comprising (a) a nucleic acid molecule comprising a nucleic acid sequence that encodes an amino acid sequence of SEQ ID NO: 172 through 295; (b) a nucleic acid molecule comprising a nucleic acid sequence of SEQ ID NO: 1 through 171; (c) a nucleic acid molecule that selectively hybridizes to the nucleic acid molecule of (a) or (b); or (d) a nucleic acid molecule having at least 60% sequence identity to the nucleic acid molecule of (a) or (b).
 2. The nucleic acid molecule according to claim 1, wherein the nucleic acid molecule is a cDNA.
 3. The nucleic acid molecule according to claim 1, wherein the nucleic acid molecule is genomic DNA.
 4. The nucleic acid molecule according to claim 1, wherein the nucleic acid molecule is a mammalian nucleic acid molecule.
 5. The nucleic acid molecule according to claim 4, wherein the nucleic acid molecule is a human nucleic acid molecule.
 6. A method for determining the presence of a breast specific nucleic acid (BSNA) in a sample, comprising the steps of: (a) contacting the sample with the nucleic acid molecule according to claim 1 under conditions in which the nucleic acid molecule will selectively hybridize to a breast specific nucleic acid; and (b) detecting hybridization of the nucleic acid molecule to a BSNA in the sample, wherein the detection of the hybridization indicates the presence of a BSNA in the sample.
 7. A vector comprising the nucleic acid molecule of claim
 1. 8. A host cell comprising the vector according to claim
 7. 9. A method for producing a polypeptide encoded by the nucleic acid molecule according to claim 1, comprising the steps of (a) providing a host cell comprising the nucleic acid molecule operably linked to one or more expression control sequences, and (b) incubating the host cell under conditions in which the polypeptide is produced.
 10. A polypeptide encoded by the nucleic acid molecule according to claim
 1. 11. An isolated polypeptide selected from the group consisting of: (a) a polypeptide comprising an amino acid sequence with at least 60% sequence identity to of SEQ ID NO: 172 through 295; or (b) a polypeptide comprising an amino acid sequence encoded by a nucleic acid molecule comprising a nucleic acid sequence of SEQ ID NO: 1 through
 171. 12. An antibody or fragment thereof that specifically binds to the polypeptide according to claim
 11. 13. A method for determining the presence of a breast specific protein in a sample, comprising the steps of: (a) contacting the sample with the antibody according to claim 12 under conditions in which the antibody will selectively bind to the breast specific protein; and (b) detecting binding of the antibody to a breast specific protein in the sample, wherein the detection of binding indicates the presence of a breast specific protein in the sample.
 14. A method for diagnosing and monitoring the presence and metastases of breast cancer in a patient, comprising the steps of: (a) determining an amount of the nucleic acid molecule of claim 1 or a polypeptide of claim 11 in a sample of a patient; and (b) comparing the amount of the determined nucleic acid molecule or the polypeptide in the sample of the patient to the amount of the breast specific marker in a normal control; wherein a difference in the amount of the nucleic acid molecule or the polypeptide in the sample compared to the amount of the nucleic acid molecule or the polypeptide in the normal control is associated with the presence of breast cancer.
 15. A kit for detecting a risk of cancer or presence of cancer in a patient, said kit comprising a means for determining the presence the nucleic acid molecule of claim 1 or a polypeptide of claim 11 in a sample of a patient.
 16. A method of treating a patient with breast cancer, comprising the step of administering a composition according to claim 12 to a patient in need thereof, wherein said administration induces an immune response against the breast cancer cell expressing the nucleic acid molecule or polypeptide.
 17. A vaccine comprising the polypeptide or the nucleic acid encoding the polypeptide of claim
 11. 